{ "$schema_version": "5.3", "review_mode": "fresh", "claim_restatement": { "index_wording": "Diet–Heart (Saturated Fat) Hypothesis", "entry_form": "claim", "gradeable_restatement": "Replacing cis-unsaturated dietary fats with saturated fats causally increases ASCVD risk through elevation of LDL/apoB particles.", "restatement_required": true, "split_into": [], "parent_claim": null, "scope_qualifiers": [ { "qualifier": "Genotype, species, tissue, baseline eligibility and treatment timing fixed before outcomes", "determinable_before_outcome": true, "determined_from": "Enrollment and experimental design, before results; no responder-defined scope.", "action": "retained" } ] }, "hypothesis": { "name": "Diet–Heart (Saturated Fat) Hypothesis", "central_claim": "Replacing cis-unsaturated dietary fats with saturated fats causally increases ASCVD risk through elevation of LDL/apoB particles.", "proposed_mechanism": "Replacing cis-unsaturated dietary fats with saturated fats causally increases ASCVD risk through elevation of LDL/apoB particles.", "claimed_scope": "Isoenergetic saturated-for-cis-unsaturated replacement and particle-mediated ASCVD risk; food matrix, fatty-acid species and baseline risk remain explicit", "claimed_level": [ "initiation", "progression" ], "is_conjunctive": true, "conjunctive_note": "SC3 is the clinical causal claim at the registered scope; narrower molecular, treatment or inherited-syndrome findings cannot replace it. Primary-subclaim aggregation is fixed before grading." }, "rubric_routing": { "primary_rubric": "06-metabolism-aging.md", "secondary_rubrics": [], "index_notes_applied": [ "SC3 is the clinical causal claim at the registered scope; narrower molecular, treatment or inherited-syndrome findings cannot replace it. Primary-subclaim aggregation is fixed before grading." ], "rubric_fit_note": "06-metabolism-aging is the registered closest rubric, although ASCVD nutrition is not a lifespan hypothesis. Its functional endpoint is explicitly operationalized as clinical ASCVD rather than requiring lifespan extension. SC1 alone remains biomarker-limited; SC2 clinical events and SC3 assembled dietary/particle inference receive separate adjudication. The adaptation is visible and should receive independent reviewer scrutiny." }, "subclaim_matrix": { "subclaims": [ { "id": "SC1", "statement": "Isoenergetic saturated-fat replacement of cis-unsaturated fat raises LDL/apoB under controlled dietary conditions.", "subclaim_type": "mechanism", "scope": "Replacement nutrient and dietary pattern defined before outcomes", "claimed_scope": "Replacement nutrient and dietary pattern defined before outcomes", "governing_rubric": "06-metabolism-aging.md", "key_evidence_anchor": "Controlled feeding and randomized dietary replacement", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Controlled feeding demonstrates a real biochemical LDL/apoB response, with heterogeneous responses across food matrices and comparators. The isolated SC1 evidence has biomarker endpoints, so the aging rubric functional-phenotype ceiling is Γ; this letter does not deny causality of the measured lipid response." }, { "id": "SC2", "statement": "Higher cumulative LDL/apoB exposure causally increases ASCVD risk.", "subclaim_type": "necessity", "scope": "Clinical atherosclerotic disease, with particle exposure and timing specified", "claimed_scope": "Clinical atherosclerotic disease, with particle exposure and timing specified", "governing_rubric": "06-metabolism-aging.md", "key_evidence_anchor": "Genetic, natural-experiment and pharmacological clinical evidence", "hsef_level": "Η", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Randomized clinical particle-lowering, human causal genetics and lifelong hypercholesterolemia converge on apoB-particle contribution to ASCVD. Different genotypes, drug strategies and clinical settings constrain distinct errors. Dietary trial conflicts do not overturn this independently supported causal component." }, { "id": "SC3", "statement": "Saturated-for-unsaturated fat replacement raises clinical ASCVD risk through this lipid pathway.", "subclaim_type": "generalization", "scope": "Defined nutrient replacement rather than unrestricted food/category comparison", "claimed_scope": "Defined nutrient replacement rather than unrestricted food/category comparison", "governing_rubric": "06-metabolism-aging.md", "key_evidence_anchor": "Randomized dietary clinical endpoints with adherence and lipid measurements", "hsef_level": "Ε", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "The assembled replacement, particle-causal and clinical-dietary evidence supports context-specific particle-mediated risk. It is stronger than biomarkers alone when read as a complementary causal set, but direct diet-specific clinical mediation, universal food-class effects and equally supported MUFA/PUFA event benefits remain unresolved. Clinical dietary patterns and historical replacements map restricted context rather than a universal guaranteed outcome." } ], "aggregation_rule": "primary-subclaim", "aggregation_preregistered": true, "aggregation_rationale": "SC3 is the clinical causal claim at the registered scope; narrower molecular, treatment or inherited-syndrome findings cannot replace it. Primary-subclaim aggregation is fixed before grading.", "primary_subclaim_id": "SC3", "aggregation_derivation": "Overall Ε follows preregistered SC3. The isolated biomarker component is Γ and the independently convergent particle-to-ASCVD component is Η. SC3 is assessed on their assembled complementary evidence with clinical dietary results, not by reimposing the biomarker cap on the whole set. Comparator-specific effects, historical endpoint conflicts, food matrix and uncertain selective mediation prevent broad diet-specific Ζ. This remains a bounded reviewer judgement, not a numerical estimate of individual risk.", "aggregation_alternatives": { "weakest_link_would_return": "Γ", "primary_subclaim_would_return": "Ε", "scope_matched_would_return": "Ε", "note": "Separate narrow successes do not replace the preregistered gate." }, "index_rule_deviation": "" }, "competing_models": { "models_evaluated": [ { "rank_in_tournament": 1, "model_id": "M2", "is_nominal": false, "name": "Replacement-nutrient and food-matrix model", "core_claim": "Net risk depends on which foods/fatty acids replace which nutrients, with the particle pathway as a causal component.", "explains_what_nominal_does_not": "Net risk depends on which foods/fatty acids replace which nutrients, with the particle pathway as a causal component.", "strongest_supporting_evidence": [ "Feeding heterogeneity, substitution cohorts and dietary endpoint contrasts explain comparator-specific effects." ], "strongest_contradictory_evidence": [ "No complete food-specific causal map or selective clinical mediation estimate exists." ], "hsef_level_for_this_model": "Ε", "rationale": "Feeding heterogeneity, substitution cohorts and dietary endpoint contrasts explain comparator-specific effects. No complete food-specific causal map or selective clinical mediation estimate exists." }, { "rank_in_tournament": 2, "model_id": "M1", "is_nominal": true, "name": "Saturated-fat–LDL risk model", "core_claim": "Sustained SFA-for-cis-UFA replacement elevates particles and thereby contributes to ASCVD.", "explains_what_nominal_does_not": "Sustained SFA-for-cis-UFA replacement elevates particles and thereby contributes to ASCVD.", "strongest_supporting_evidence": [ "Controlled lipid effects and independent particle-lowering/genetic clinical evidence strongly support the causal chain." ], "strongest_contradictory_evidence": [ "Uniform net effects and diet-specific attribution are weaker than particle causality." ], "hsef_level_for_this_model": "Ε", "rationale": "Controlled lipid effects and independent particle-lowering/genetic clinical evidence strongly support the causal chain. Uniform net effects and diet-specific attribution are weaker than particle causality." }, { "rank_in_tournament": 3, "model_id": "M3", "is_nominal": false, "name": "LDL-independent dietary pathways", "core_claim": "Foods also act through weight, metabolism, inflammation and other pathways.", "explains_what_nominal_does_not": "Foods also act through weight, metabolism, inflammation and other pathways.", "strongest_supporting_evidence": [ "Multifactor interventions and metabolic responses provide plausible additional routes." ], "strongest_contradictory_evidence": [ "Those routes do not make apoB particles noncausal and are incompletely isolated." ], "hsef_level_for_this_model": "Γ", "rationale": "Multifactor interventions and metabolic responses provide plausible additional routes. Those routes do not make apoB particles noncausal and are incompletely isolated." }, { "rank_in_tournament": 4, "model_id": "M4", "is_nominal": false, "name": "Observational-confounding explanation", "core_claim": "Dietary associations reflect socioeconomic and behavioural confounding.", "explains_what_nominal_does_not": "Dietary associations reflect socioeconomic and behavioural confounding.", "strongest_supporting_evidence": [ "Cohorts and adherence analyses have substantial shared vulnerabilities." ], "strongest_contradictory_evidence": [ "Confounding alone does not explain controlled feeding and randomized particle-lowering clinical effects." ], "hsef_level_for_this_model": "Β", "rationale": "Cohorts and adherence analyses have substantial shared vulnerabilities. Confounding alone does not explain controlled feeding and randomized particle-lowering clinical effects." } ], "tournament_summary": "Descriptive comparison; does not modify the nominal score. The randomized coconut/olive/butter comparison (PMID29511019) and palm/cocoa-butter comparison (PMID31227804) best discriminate matrix-specific lipid effects from a uniform saturated-fat-class model. Neither supplies a clinical-event separator. DIVAS (PMID26016869) separates lipid benefit from its null primary vascular endpoint, while particle trials establish a different causal link.", "study_separating_rank1_from_rank2": "The randomized coconut/olive/butter comparison (PMID29511019) and palm/cocoa-butter comparison (PMID31227804) best discriminate matrix-specific lipid effects from a uniform saturated-fat-class model. Neither supplies a clinical-event separator. DIVAS (PMID26016869) separates lipid benefit from its null primary vascular endpoint, while particle trials establish a different causal link.", "nominal_wins_only_by_funding_artifact": false, "level_unchanged_by_tournament": true }, "evidence_inventory": [ { "n": 1, "pmid": "32209700", "title": "Dietary Fats and Atherosclerosis From Childhood to Adulthood.", "citation": "Laitinen TT, Nuotio J, Rovio SP et al. Dietary Fats and Atherosclerosis From Childhood to Adulthood. Pediatrics. 2020.", "doi": "10.1542/peds.2019-2786", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/32209700/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32209700/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "STRIP", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Achieving STRIP dietary targets associates with better aortic structure and distensibility.", "what_it_does_not_show": "Target attainment is not randomized; shared parent cohort and surrogate vascular outcomes.", "confounders_present": [ "Target attainment is not randomized; shared parent cohort and surrogate vascular outcomes." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 2, "pmid": "393644", "title": "Dietary prevention of coronary heart disease: the Finnish Mental Hospital Study.", "citation": "Turpeinen O, Karvonen MJ, Pekkarinen M et al. Dietary prevention of coronary heart disease: the Finnish Mental Hospital Study. International journal of epidemiology. 1979.", "doi": "10.1093/ije/8.2.99", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/393644/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/393644/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID393644", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Finnish hospital diet periods with lower saturated fat/cholesterol show lower serum cholesterol and coronary incidence.", "what_it_does_not_show": "Hospital-period crossover, changing admissions and multifactor diet prevent clean individual randomization or selective fat mediation.", "confounders_present": [ "Hospital-period crossover, changing admissions and multifactor diet prevent clean individual randomization or selective fat mediation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 3, "pmid": "30072407", "title": "Success in Achieving the Targets of the 20-Year Infancy-Onset Dietary Intervention: Association With Insulin Sensitivity and Serum Lipids.", "citation": "Laitinen TT, Nuotio J, Juonala M et al. Success in Achieving the Targets of the 20-Year Infancy-Onset Dietary Intervention: Association With Insulin Sensitivity and Serum Lipids. Diabetes care. 2018.", "doi": "10.2337/dc18-0869", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/30072407/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30072407/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "STRIP", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "STRIP target achievement associates with improved lipids and insulin sensitivity.", "what_it_does_not_show": "Postrandomization adherence comparison; shares recruitment with PMID32209700 and changes fibre too.", "confounders_present": [ "Postrandomization adherence comparison; shares recruitment with PMID32209700 and changes fibre too." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 4, "pmid": "3773141", "title": "Comparison of three cholesterol-lowering diets in normolipidemic men.", "citation": "Grundy SM, Nix D, Whelan MF et al. Comparison of three cholesterol-lowering diets in normolipidemic men. JAMA. 1986.", "doi": "", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/3773141/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/3773141/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID3773141", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Three replacement diets lower LDL in a small domiciliary feeding study.", "what_it_does_not_show": "Very small sample; multiple macronutrient changes and no coronary endpoints.", "confounders_present": [ "Very small sample; multiple macronutrient changes and no coronary endpoints." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 5, "pmid": "41390743", "title": "Effects of an anti-lipogenic low-carbohydrate high polyunsaturated fat diet or a healthy Nordic diet versus usual care on liver fat and cardiometabolic disorders in type 2 diabetes or prediabetes: a randomized controlled trial (NAFLDiet).", "citation": "Fridén M, Rosqvist F, Kullberg J et al. Effects of an anti-lipogenic low-carbohydrate high polyunsaturated fat diet or a healthy Nordic diet versus usual care on liver fat and cardiometabolic disorders in type 2 diabetes or prediabetes: a randomized controlled trial (NAFLDiet). Nature communications. 2025.", "doi": "10.1038/s41467-025-65613-2", "pmcid": "PMC12705689", "url": "https://pubmed.ncbi.nlm.nih.gov/41390743/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41390743/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID41390743", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "LCPUFA and Nordic diets reduce LDL and liver fat versus usual care in metabolic disease.", "what_it_does_not_show": "Ad-libitum dietary patterns and differing weight changes; no selective saturated-fat clinical-outcome attribution.", "confounders_present": [ "Ad-libitum dietary patterns and differing weight changes; no selective saturated-fat clinical-outcome attribution." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 6, "pmid": "3511692", "title": "Oslo Study Diet and Antismoking Trial. Results after 102 months.", "citation": "Hjermann I, Holme I, Leren P. Oslo Study Diet and Antismoking Trial. Results after 102 months. The American journal of medicine. 1986.", "doi": "10.1016/0002-9343(86)90154-3", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/3511692/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/3511692/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID3511692", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Oslo diet/antismoking intervention retains lower coronary-event rates on follow-up.", "what_it_does_not_show": "Diet and smoking were changed together; clinical benefit is not exclusively saturated-fat replacement.", "confounders_present": [ "Diet and smoking were changed together; clinical benefit is not exclusively saturated-fat replacement." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 7, "pmid": "33801247", "title": "A Ketogenic Low-Carbohydrate High-Fat Diet Increases LDL Cholesterol in Healthy, Young, Normal-Weight Women: A Randomized Controlled Feeding Trial.", "citation": "Burén J, Ericsson M, Damasceno NRT et al. A Ketogenic Low-Carbohydrate High-Fat Diet Increases LDL Cholesterol in Healthy, Young, Normal-Weight Women: A Randomized Controlled Feeding Trial. Nutrients. 2021.", "doi": "10.3390/nu13030814", "pmcid": "PMC8001988", "url": "https://pubmed.ncbi.nlm.nih.gov/33801247/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33801247/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID33801247", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Ketogenic high-fat feeding raises LDL and apoB in young normal-weight women.", "what_it_does_not_show": "Carbohydrate, total fat and fatty-acid composition all change; incomplete retention and short duration.", "confounders_present": [ "Carbohydrate, total fat and fatty-acid composition all change; incomplete retention and short duration." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 8, "pmid": "34582545", "title": "Effects of a low-carbohydrate diet on insulin-resistant dyslipoproteinemia-a randomized controlled feeding trial.", "citation": "Ebbeling CB, Knapp A, Johnson A et al. Effects of a low-carbohydrate diet on insulin-resistant dyslipoproteinemia-a randomized controlled feeding trial. The American journal of clinical nutrition. 2022.", "doi": "10.1093/ajcn/nqab287", "pmcid": "PMC8755039", "url": "https://pubmed.ncbi.nlm.nih.gov/34582545/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34582545/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "ErratumIn: PMID35022668" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID34582545", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "High-saturated-fat low-carbohydrate feeding improves selected lipid traits without an LDL increase versus comparators.", "what_it_does_not_show": "Carbohydrate replacement differs from fixed cis-unsaturated replacement; linked correction details not examined.", "confounders_present": [ "Carbohydrate replacement differs from fixed cis-unsaturated replacement; linked correction details not examined." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 9, "pmid": "31227804", "title": "Fatty acid regio-specificity of triacylglycerol molecules may affect plasma lipid responses to dietary fats-a randomised controlled cross-over trial.", "citation": "Stonehouse W, Benassi-Evans B, James-Martin G et al. Fatty acid regio-specificity of triacylglycerol molecules may affect plasma lipid responses to dietary fats-a randomised controlled cross-over trial. European journal of clinical nutrition. 2020.", "doi": "10.1038/s41430-019-0452-7", "pmcid": "PMC7007409", "url": "https://pubmed.ncbi.nlm.nih.gov/31227804/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31227804/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID31227804", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "null", "what_it_shows": "Palm/cocoa-butter and olive-oil diets have similar tested lipid responses in young participants.", "what_it_does_not_show": "Fatty-acid positioning and limited sample/time constrain universal fat-class predictions.", "confounders_present": [ "Fatty-acid positioning and limited sample/time constrain universal fat-class predictions." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 10, "pmid": "26429077", "title": "Saturated Fats Compared With Unsaturated Fats and Sources of Carbohydrates in Relation to Risk of Coronary Heart Disease: A Prospective Cohort Study.", "citation": "Li Y, Hruby A, Bernstein AM et al. Saturated Fats Compared With Unsaturated Fats and Sources of Carbohydrates in Relation to Risk of Coronary Heart Disease: A Prospective Cohort Study. Journal of the American College of Cardiology. 2015.", "doi": "10.1016/j.jacc.2015.07.055", "pmcid": "PMC4593072", "url": "https://pubmed.ncbi.nlm.nih.gov/26429077/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26429077/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID26429077", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Cohort substitution models associate replacing SFA with PUFA/MUFA with lower CHD risk.", "what_it_does_not_show": "Diet-reporting, residual confounding and overlapping US cohorts; modeled exchange is not randomized.", "confounders_present": [ "Diet-reporting, residual confounding and overlapping US cohorts; modeled exchange is not randomized." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 11, "pmid": "27557656", "title": "Dairy fat and risk of cardiovascular disease in 3 cohorts of US adults.", "citation": "Chen M, Li Y, Sun Q et al. Dairy fat and risk of cardiovascular disease in 3 cohorts of US adults. The American journal of clinical nutrition. 2016.", "doi": "10.3945/ajcn.116.134460", "pmcid": "PMC5081717", "url": "https://pubmed.ncbi.nlm.nih.gov/27557656/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27557656/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID27557656", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Dairy-fat substitution risk differs by replacement nutrient; PUFA replacement associates with lower CVD.", "what_it_does_not_show": "Dairy versus carbohydrate is not the nominal comparison; overlaps US cohort resources.", "confounders_present": [ "Dairy versus carbohydrate is not the nominal comparison; overlaps US cohort resources." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 12, "pmid": "30167851", "title": "Fatty acids from dairy and meat and their association with risk of coronary heart disease.", "citation": "Vissers LET, Rijksen J, Boer JMA et al. Fatty acids from dairy and meat and their association with risk of coronary heart disease. European journal of nutrition. 2019.", "doi": "10.1007/s00394-018-1811-1", "pmcid": "PMC6768909", "url": "https://pubmed.ncbi.nlm.nih.gov/30167851/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30167851/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID30167851", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Meat-versus-dairy SFA substitution associates with different coronary risk.", "what_it_does_not_show": "Observational food-matrix differences and residual confounding; cannot isolate fatty acids alone.", "confounders_present": [ "Observational food-matrix differences and residual confounding; cannot isolate fatty acids alone." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 13, "pmid": "39279644", "title": "Saturated fatty acids and total and CVD mortality in Norway: a prospective cohort study with up to 45 years of follow-up.", "citation": "Arnesen EK, Laake I, Veierød MB et al. Saturated fatty acids and total and CVD mortality in Norway: a prospective cohort study with up to 45 years of follow-up. The British journal of nutrition. 2024.", "doi": "10.1017/S0007114524001351", "pmcid": "PMC11499087", "url": "https://pubmed.ncbi.nlm.nih.gov/39279644/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39279644/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID39279644", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Long-term Norwegian data associate higher SFA intake with mortality and model benefit of replacement.", "what_it_does_not_show": "Measurement error, secular changes and residual confounding; theoretical exchange is not an intervention.", "confounders_present": [ "Measurement error, secular changes and residual confounding; theoretical exchange is not an intervention." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 14, "pmid": "32203549", "title": "Evaluating the relationship between circulating lipoprotein lipids and apolipoproteins with risk of coronary heart disease: A multivariable Mendelian randomisation analysis.", "citation": "Richardson TG, Sanderson E, Palmer TM et al. Evaluating the relationship between circulating lipoprotein lipids and apolipoproteins with risk of coronary heart disease: A multivariable Mendelian randomisation analysis. PLoS medicine. 2020.", "doi": "10.1371/journal.pmed.1003062", "pmcid": "PMC7089422", "url": "https://pubmed.ncbi.nlm.nih.gov/32203549/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32203549/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID32203549", "access_depth": "full_text_partial", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 2:Results:paragraph7. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "natural experiment", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Multivariable MR prioritizes apoB for CHD over correlated lipid measures.", "what_it_does_not_show": "Instrument validity, collinearity and shared GWAS restrict exclusive mediation interpretation.", "confounders_present": [ "Instrument validity, collinearity and shared GWAS restrict exclusive mediation interpretation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [ "Shared UK Biobank participants and/or lipid GWAS instruments; not automatically independent clinical causal evidence." ] }, { "n": 15, "pmid": "33130851", "title": "High-throughput multivariable Mendelian randomization analysis prioritizes apolipoprotein B as key lipid risk factor for coronary artery disease.", "citation": "Zuber V, Gill D, Ala-Korpela M et al. High-throughput multivariable Mendelian randomization analysis prioritizes apolipoprotein B as key lipid risk factor for coronary artery disease. International journal of epidemiology. 2021.", "doi": "10.1093/ije/dyaa216", "pmcid": "PMC8271202", "url": "https://pubmed.ncbi.nlm.nih.gov/33130851/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33130851/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID33130851", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "natural experiment", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Agnostic multivariable genetic analysis consistently prioritizes apoB for coronary disease.", "what_it_does_not_show": "Shared genetic resources and instrument assumptions; not an independent dietary experiment.", "confounders_present": [ "Shared genetic resources and instrument assumptions; not an independent dietary experiment." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [ "Shared UK Biobank participants and/or lipid GWAS instruments; not automatically independent clinical causal evidence." ] }, { "n": 16, "pmid": "30694319", "title": "Association of Triglyceride-Lowering LPL Variants and LDL-C-Lowering LDLR Variants With Risk of Coronary Heart Disease.", "citation": "Ference BA, Kastelein JJP, Ray KK et al. Association of Triglyceride-Lowering LPL Variants and LDL-C-Lowering LDLR Variants With Risk of Coronary Heart Disease. JAMA. 2019.", "doi": "10.1001/jama.2018.20045", "pmcid": "PMC6439767", "url": "https://pubmed.ncbi.nlm.nih.gov/30694319/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30694319/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID30694319", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "natural experiment", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "LPL and LDLR genetic scores yield similar lower CHD risk per apoB decrement despite differing cholesterol/triglyceride effects.", "what_it_does_not_show": "Lifelong genetic exposure and pleiotropy; does not estimate a food-substitution treatment effect.", "confounders_present": [ "Lifelong genetic exposure and pleiotropy; does not estimate a food-substitution treatment effect." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [] }, { "n": 17, "pmid": "38241044", "title": "Dose-Response Associations of Lipid Traits With Coronary Artery Disease and Mortality.", "citation": "Yang G, Mason AM, Wood AM et al. Dose-Response Associations of Lipid Traits With Coronary Artery Disease and Mortality. JAMA network open. 2024.", "doi": "10.1001/jamanetworkopen.2023.52572", "pmcid": "PMC10799266", "url": "https://pubmed.ncbi.nlm.nih.gov/38241044/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38241044/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID38241044", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "natural experiment", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Genetically predicted apoB and LDL associate with coronary disease and mortality across dose ranges.", "what_it_does_not_show": "Selection and nonlinear-MR assumptions; triglyceride pleiotropy and overlapping resources remain.", "confounders_present": [ "Selection and nonlinear-MR assumptions; triglyceride pleiotropy and overlapping resources remain." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [ "Shared UK Biobank participants and/or lipid GWAS instruments; not automatically independent clinical causal evidence." ] }, { "n": 18, "pmid": "38102060", "title": "The relationship between genetic liver fat and coronary heart disease is explained by apoB-containing lipoproteins.", "citation": "Björnson E, Adiels M, Bergström G et al. The relationship between genetic liver fat and coronary heart disease is explained by apoB-containing lipoproteins. Atherosclerosis. 2024.", "doi": "10.1016/j.atherosclerosis.2023.117397", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/38102060/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38102060/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID38102060", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "natural experiment", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Liver-fat genetic clusters show coronary-risk directions aligning with apoB changes.", "what_it_does_not_show": "Statistical mediation and pleiotropy cannot establish all biological pathways or dietary specificity.", "confounders_present": [ "Statistical mediation and pleiotropy cannot establish all biological pathways or dietary specificity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [ "Shared UK Biobank participants and/or lipid GWAS instruments; not automatically independent clinical causal evidence." ] }, { "n": 19, "pmid": "38233012", "title": "Lipoprotein(a) Is Markedly More Atherogenic Than LDL: An Apolipoprotein B-Based Genetic Analysis.", "citation": "Björnson E, Adiels M, Taskinen MR et al. Lipoprotein(a) Is Markedly More Atherogenic Than LDL: An Apolipoprotein B-Based Genetic Analysis. Journal of the American College of Cardiology. 2024.", "doi": "10.1016/j.jacc.2023.10.039", "pmcid": "PMC7616706", "url": "https://pubmed.ncbi.nlm.nih.gov/38233012/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38233012/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID38233012", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "natural experiment", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Genetic analysis estimates greater CHD atherogenicity per Lp(a)-apoB particle than LDL-apoB.", "what_it_does_not_show": "Particle types are not interchangeable; assumptions and populations constrain the magnitude estimate.", "confounders_present": [ "Particle types are not interchangeable; assumptions and populations constrain the magnitude estimate." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [ "Shared UK Biobank participants and/or lipid GWAS instruments; not automatically independent clinical causal evidence." ] }, { "n": 20, "pmid": "37358553", "title": "Triglyceride-rich lipoprotein remnants, low-density lipoproteins, and risk of coronary heart disease: a UK Biobank study.", "citation": "Björnson E, Adiels M, Taskinen MR et al. Triglyceride-rich lipoprotein remnants, low-density lipoproteins, and risk of coronary heart disease: a UK Biobank study. European heart journal. 2023.", "doi": "10.1093/eurheartj/ehad337", "pmcid": "PMC10576615", "url": "https://pubmed.ncbi.nlm.nih.gov/37358553/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37358553/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID37358553", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "natural experiment", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Remnant-associated genetic clusters show greater coronary-risk effects per apoB than LDL-associated clusters.", "what_it_does_not_show": "Shared UK Biobank and differing pathways; not all apoB particles have equal risk weights.", "confounders_present": [ "Shared UK Biobank and differing pathways; not all apoB particles have equal risk weights." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [ "Shared UK Biobank participants and/or lipid GWAS instruments; not automatically independent clinical causal evidence." ] }, { "n": 21, "pmid": "40105833", "title": "Joint Associations of APOC3 and LDL-C-Lowering Variants With the Risk of Coronary Heart Disease.", "citation": "Wang W, Li R, Song Z et al. Joint Associations of APOC3 and LDL-C-Lowering Variants With the Risk of Coronary Heart Disease. JAMA cardiology. 2025.", "doi": "10.1001/jamacardio.2025.0195", "pmcid": "PMC11923777", "url": "https://pubmed.ncbi.nlm.nih.gov/40105833/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40105833/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID40105833", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "natural experiment", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "APOC3 and LDL-lowering genetic variants show additive CHD associations aligned with apoB.", "what_it_does_not_show": "Drug-target genetic proxies are lifelong and partly pleiotropic; not randomized therapy or diet.", "confounders_present": [ "Drug-target genetic proxies are lifelong and partly pleiotropic; not randomized therapy or diet." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [ "Shared UK Biobank participants and/or lipid GWAS instruments; not automatically independent clinical causal evidence." ] }, { "n": 22, "pmid": "36031810", "title": "Long-Term Evolocumab in Patients With Established Atherosclerotic Cardiovascular Disease.", "citation": "O'Donoghue ML, Giugliano RP, Wiviott SD et al. Long-Term Evolocumab in Patients With Established Atherosclerotic Cardiovascular Disease. Circulation. 2022.", "doi": "10.1161/CIRCULATIONAHA.122.061620", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/36031810/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36031810/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "FOURIER", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "FOURIER extension shows durable low LDL and lower events by original treatment allocation.", "what_it_does_not_show": "Selected open-label extension with both groups treated; not a new independent randomization.", "confounders_present": [ "Selected open-label extension with both groups treated; not a new independent randomization." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 23, "pmid": "35863366", "title": "Long-term efficacy and safety of moderate-intensity statin with ezetimibe combination therapy versus high-intensity statin monotherapy in patients with atherosclerotic cardiovascular disease (RACING): a randomised, open-label, non-inferiority trial.", "citation": "Kim BK, Hong SJ, Lee YJ et al. Long-term efficacy and safety of moderate-intensity statin with ezetimibe combination therapy versus high-intensity statin monotherapy in patients with atherosclerotic cardiovascular disease (RACING): a randomised, open-label, non-inferiority trial. Lancet (London, England). 2022.", "doi": "10.1016/S0140-6736(22)00916-3", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/35863366/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35863366/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID35863366", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. 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Association of Monogenic vs Polygenic Hypercholesterolemia With Risk of Atherosclerotic Cardiovascular Disease. JAMA cardiology. 2020.", "doi": "10.1001/jamacardio.2019.5954", "pmcid": "PMC7042820", "url": "https://pubmed.ncbi.nlm.nih.gov/32049305/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32049305/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID32159730" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID32049305", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "natural experiment", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Monogenic and polygenic hypercholesterolemia associate with higher ASCVD risk even at comparable measured LDL.", "what_it_does_not_show": "Lifetime exposure differs from single measurement; selected genotype groups and linked erratum require caution.", "confounders_present": [ "Lifetime exposure differs from single measurement; selected genotype groups and linked erratum require caution." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [ "Shared UK Biobank participants and/or lipid GWAS instruments; not automatically independent clinical causal evidence." ] }, { "n": 30, "pmid": "34297352", "title": "Genetic spectrum of familial hypercholesterolemia and correlations with clinical expression: Implications for diagnosis improvement.", "citation": "Di Taranto MD, Giacobbe C, Palma D et al. Genetic spectrum of familial hypercholesterolemia and correlations with clinical expression: Implications for diagnosis improvement. Clinical genetics. 2021.", "doi": "10.1111/cge.14036", "pmcid": "PMC9291778", "url": "https://pubmed.ncbi.nlm.nih.gov/34297352/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34297352/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID34297352", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. 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Association Between Achieved Low-Density Lipoprotein Cholesterol Levels and Long-Term Cardiovascular and Safety Outcomes: An Analysis of FOURIER-OLE. Circulation. 2023.", "doi": "10.1161/CIRCULATIONAHA.122.063399", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/36779348/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36779348/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "FOURIER", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Lower achieved LDL in FOURIER-OLE associates with fewer subsequent clinical events.", "what_it_does_not_show": "Postrandomization exposure, extension selection and shared cohort; not independent randomized dose assignment.", "confounders_present": [ "Postrandomization exposure, extension selection and shared cohort; not independent randomized dose assignment." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 32, "pmid": "2643423", "title": "Test of effect of lipid lowering by diet on cardiovascular risk. The Minnesota Coronary Survey.", "citation": "Frantz ID, Dawson EA, Ashman PL et al. Test of effect of lipid lowering by diet on cardiovascular risk. The Minnesota Coronary Survey. Arteriosclerosis (Dallas, Tex.). 1989.", "doi": "10.1161/01.atv.9.1.129", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/2643423/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/2643423/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "MINNESOTA", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "null", "what_it_shows": "Minnesota dietary replacement lowers cholesterol without overall cardiovascular or mortality benefit.", "what_it_does_not_show": "Limited inpatient exposure, dietary cholesterol changes and historical food composition; shares trial with PMID27071971.", "confounders_present": [ "Limited inpatient exposure, dietary cholesterol changes and historical food composition; shares trial with PMID27071971." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 33, "pmid": "9989963", "title": "Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction: final report of the Lyon Diet Heart Study.", "citation": "de Lorgeril M, Salen P, Martin JL et al. Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction: final report of the Lyon Diet Heart Study. Circulation. 1999.", "doi": "10.1161/01.cir.99.6.779", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/9989963/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/9989963/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID9989963", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Lyon Mediterranean dietary pattern retains lower recurrent cardiovascular complications.", "what_it_does_not_show": "Multicomponent dietary pattern and secondary prevention; no selective saturated-fat/apoB mediation test.", "confounders_present": [ "Multicomponent dietary pattern and secondary prevention; no selective saturated-fat/apoB mediation test." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 34, "pmid": "24550191", "title": "Overfeeding polyunsaturated and saturated fat causes distinct effects on liver and visceral fat accumulation in humans.", "citation": "Rosqvist F, Iggman D, Kullberg J et al. Overfeeding polyunsaturated and saturated fat causes distinct effects on liver and visceral fat accumulation in humans. Diabetes. 2014.", "doi": "10.2337/db13-1622", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/24550191/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24550191/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID24550191", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Matched weight gain under SFA versus PUFA overfeeding produces different liver/visceral fat accumulation.", "what_it_does_not_show": "Excess-calorie metabolic experiment, not ordinary-energy coronary-event replacement.", "confounders_present": [ "Excess-calorie metabolic experiment, not ordinary-energy coronary-event replacement." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 35, "pmid": "32756661", "title": "Effects of plant oils with different fatty acid composition on cardiovascular risk factors in moderately hypercholesteremic Chinese adults: a randomized, double-blinded, parallel-designed trial.", "citation": "Chen CG, Wang P, Zhang ZQ et al. Effects of plant oils with different fatty acid composition on cardiovascular risk factors in moderately hypercholesteremic Chinese adults: a randomized, double-blinded, parallel-designed trial. Food & function. 2020.", "doi": "10.1039/d0fo00875c", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/32756661/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32756661/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID32756661", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "null", "what_it_shows": "Different plant cooking oils alter membrane composition without significant between-group lipid changes.", "what_it_does_not_show": "All comparators are plant oils; no direct saturated-versus-cis-unsaturated contrast or clinical endpoints.", "confounders_present": [ "All comparators are plant oils; no direct saturated-versus-cis-unsaturated contrast or clinical endpoints." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 36, "pmid": "40339906", "title": "Impact of dietary cholesterol from eggs and saturated fat on LDL cholesterol levels: a randomized cross-over study.", "citation": "Carter S, Hill AM, Yandell C et al. Impact of dietary cholesterol from eggs and saturated fat on LDL cholesterol levels: a randomized cross-over study. The American journal of clinical nutrition. 2025.", "doi": "10.1016/j.ajcnut.2025.05.001", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/40339906/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40339906/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "ErratumIn: PMID41138747" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID40339906", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Low-SFA egg-containing feeding lowers LDL versus high-SFA control, with particle-subfraction changes.", "what_it_does_not_show": "Eggs and fat composition change together; linked erratum not examined and no measured event reduction.", "confounders_present": [ "Eggs and fat composition change together; linked erratum not examined and no measured event reduction." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 37, "pmid": "28864332", "title": "Associations of fats and carbohydrate intake with cardiovascular disease and mortality in 18 countries from five continents (PURE): a prospective cohort study.", "citation": "Dehghan M, Mente A, Zhang X et al. Associations of fats and carbohydrate intake with cardiovascular disease and mortality in 18 countries from five continents (PURE): a prospective cohort study. Lancet (London, England). 2017.", "doi": "10.1016/S0140-6736(17)32252-3", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/28864332/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28864332/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID28864332", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "PURE associates higher fat intake with lower total mortality and no clear MI/CVD-mortality association.", "what_it_does_not_show": "Carbohydrate comparison and socioeconomic/energy confounding differ from fixed cis-unsaturated replacement.", "confounders_present": [ "Carbohydrate comparison and socioeconomic/energy confounding differ from fixed cis-unsaturated replacement." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 38, "pmid": "32188587", "title": "Associations of fat and carbohydrate intake with cardiovascular disease and mortality: prospective cohort study of UK Biobank participants.", "citation": "Ho FK, Gray SR, Welsh P et al. Associations of fat and carbohydrate intake with cardiovascular disease and mortality: prospective cohort study of UK Biobank participants. BMJ (Clinical research ed.). 2020.", "doi": "10.1136/bmj.m688", "pmcid": "PMC7190059", "url": "https://pubmed.ncbi.nlm.nih.gov/32188587/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32188587/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID32371385" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID32188587", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "UK Biobank macronutrient associations are nonlinear and depend on intake range.", "what_it_does_not_show": "Diet assessment and residual confounding; correction details not examined and cohort overlaps genetic analyses.", "confounders_present": [ "Diet assessment and residual confounding; correction details not examined and cohort overlaps genetic analyses." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [ "Shared UK Biobank participants and/or lipid GWAS instruments; not automatically independent clinical causal evidence." ] }, { "n": 39, "pmid": "28356271", "title": "Cashew consumption reduces total and LDL cholesterol: a randomized, crossover, controlled-feeding trial.", "citation": "Mah E, Schulz JA, Kaden VN et al. Cashew consumption reduces total and LDL cholesterol: a randomized, crossover, controlled-feeding trial. The American journal of clinical nutrition. 2017.", "doi": "10.3945/ajcn.116.150037", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/28356271/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28356271/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID28356271", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Cashew feeding lowers LDL relative to a potato-chip snack comparator.", "what_it_does_not_show": "Carbohydrate/food-matrix replacement, not selective SFA exchange; short-term biomarkers.", "confounders_present": [ "Carbohydrate/food-matrix replacement, not selective SFA exchange; short-term biomarkers." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 40, "pmid": "3185285", "title": "The effects of omega 3 and omega 6 fatty acid-enriched diets on plasma lipoproteins and apoproteins in familial combined hyperlipidemia.", "citation": "Failor RA, Childs MT, Bierman EL. The effects of omega 3 and omega 6 fatty acid-enriched diets on plasma lipoproteins and apoproteins in familial combined hyperlipidemia. Metabolism: clinical and experimental. 1988.", "doi": "10.1016/0026-0495(88)90061-3", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/3185285/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/3185285/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID3185285", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "Controlled safflower/salmon diets show lipid and apoB changes differing between normal and FCHL participants.", "what_it_does_not_show": "Genotype and n-3/n-6 effects vary; no coronary endpoints or universal response.", "confounders_present": [ "Genotype and n-3/n-6 effects vary; no coronary endpoints or universal response." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 41, "pmid": "12882850", "title": "Biologic and quality-of-life outcomes from the Mediterranean Lifestyle Program: a randomized clinical trial.", "citation": "Toobert DJ, Glasgow RE, Strycker LA et al. Biologic and quality-of-life outcomes from the Mediterranean Lifestyle Program: a randomized clinical trial. Diabetes care. 2003.", "doi": "10.2337/diacare.26.8.2288", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/12882850/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/12882850/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID12882850", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "Mediterranean lifestyle program improves glycemic control and quality of life with nonsignificant lipid patterns.", "what_it_does_not_show": "Multicomponent lifestyle intervention cannot isolate dietary fat or particle-mediated ASCVD prevention.", "confounders_present": [ "Multicomponent lifestyle intervention cannot isolate dietary fat or particle-mediated ASCVD prevention." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 42, "pmid": "7930223", "title": "Development of new coronary atherosclerotic lesions during a 4-year multifactor risk reduction program: the Stanford Coronary Risk Intervention Project (SCRIP).", "citation": "Quinn TG, Alderman EL, McMillan A et al. Development of new coronary atherosclerotic lesions during a 4-year multifactor risk reduction program: the Stanford Coronary Risk Intervention Project (SCRIP). Journal of the American College of Cardiology. 1994.", "doi": "10.1016/0735-1097(94)90848-6", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/7930223/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/7930223/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID7930223", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "SCRIP multifactor intervention shows a borderline lesion-level reduction and nonsignificant patient-level new-lesion difference.", "what_it_does_not_show": "Multiple risk-factor treatments and correlated vessel segments; dietary correlation is not randomized mediation.", "confounders_present": [ "Multiple risk-factor treatments and correlated vessel segments; dietary correlation is not randomized mediation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 43, "pmid": "11288049", "title": "Effect of a very-high-fiber vegetable, fruit, and nut diet on serum lipids and colonic function.", "citation": "Jenkins DJ, Kendall CW, Popovich DG et al. Effect of a very-high-fiber vegetable, fruit, and nut diet on serum lipids and colonic function. Metabolism: clinical and experimental. 2001.", "doi": "10.1053/meta.2001.21037", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/11288049/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/11288049/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID11288049", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Weight-maintaining high-fibre vegetable/fruit/nut diet lowers LDL and changes fecal steroid loss.", "what_it_does_not_show": "Small short feeding study; fibre and food matrix prevent SFA-specific attribution or clinical-event inference.", "confounders_present": [ "Small short feeding study; fibre and food matrix prevent SFA-specific attribution or clinical-event inference." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 44, "pmid": "8506889", "title": "Response to a cholesterol-lowering diet: efficacy is greater in hypercholesterolemic subjects even after adjustment for regression to the mean.", "citation": "Denke MA, Frantz ID. Response to a cholesterol-lowering diet: efficacy is greater in hypercholesterolemic subjects even after adjustment for regression to the mean. The American journal of medicine. 1993.", "doi": "10.1016/0002-9343(93)90215-b", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/8506889/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/8506889/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID8506889", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Dietary cholesterol response differs by baseline cholesterol after accounting for regression toward the mean.", "what_it_does_not_show": "Responsiveness analysis is not a selective randomized SFA comparison or clinical endpoint test.", "confounders_present": [ "Responsiveness analysis is not a selective randomized SFA comparison or clinical endpoint test." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 45, "pmid": "29511019", "title": "Randomised trial of coconut oil, olive oil or butter on blood lipids and other cardiovascular risk factors in healthy men and women.", "citation": "Khaw KT, Sharp SJ, Finikarides L et al. Randomised trial of coconut oil, olive oil or butter on blood lipids and other cardiovascular risk factors in healthy men and women. BMJ open. 2018.", "doi": "10.1136/bmjopen-2017-020167", "pmcid": "PMC5855206", "url": "https://pubmed.ncbi.nlm.nih.gov/29511019/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29511019/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID29511019", "access_depth": "full_text_partial", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Methods:paragraph2, 1:Methods:paragraph3. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "Butter raises LDL relative to olive/coconut oils; coconut and olive responses do not differ significantly.", "what_it_does_not_show": "Free-living addition or substitution, short duration and different SFA species; no clinical events.", "confounders_present": [ "Free-living addition or substitution, short duration and different SFA species; no clinical events." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 46, "pmid": "1905474", "title": "Serum lipid and apolipoprotein concentrations in healthy men on diets enriched in either canola oil or safflower oil.", "citation": "Wardlaw GM, Snook JT, Lin MC et al. Serum lipid and apolipoprotein concentrations in healthy men on diets enriched in either canola oil or safflower oil. The American journal of clinical nutrition. 1991.", "doi": "10.1093/ajcn/54.1.104", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/1905474/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/1905474/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID1905474", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Canola/safflower diets reduce LDL and apoB versus initial American-diet baseline.", "what_it_does_not_show": "Small sample and baseline-to-intervention order; not clinical-outcome evidence.", "confounders_present": [ "Small sample and baseline-to-intervention order; not clinical-outcome evidence." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 47, "pmid": "8026287", "title": "Effect of a high-monounsaturated fat diet enriched with avocado in NIDDM patients.", "citation": "Lerman-Garber I, Ichazo-Cerro S, Zamora-González J et al. Effect of a high-monounsaturated fat diet enriched with avocado in NIDDM patients. Diabetes care. 1994.", "doi": "10.2337/diacare.17.4.311", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/8026287/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/8026287/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID8026287", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Avocado-rich MUFA replacement for carbohydrate improves selected lipids in diabetes.", "what_it_does_not_show": "Carbohydrate comparator and food matrix differ from the fixed SFA replacement question.", "confounders_present": [ "Carbohydrate comparator and food matrix differ from the fixed SFA replacement question." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 48, "pmid": "23386268", "title": "Use of dietary linoleic acid for secondary prevention of coronary heart disease and death: evaluation of recovered data from the Sydney Diet Heart Study and updated meta-analysis.", "citation": "Ramsden CE, Zamora D, Leelarthaepin B et al. Use of dietary linoleic acid for secondary prevention of coronary heart disease and death: evaluation of recovered data from the Sydney Diet Heart Study and updated meta-analysis. BMJ (Clinical research ed.). 2013.", "doi": "10.1136/bmj.e8707", "pmcid": "PMC4688426", "url": "https://pubmed.ncbi.nlm.nih.gov/23386268/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/23386268/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID not supplied" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID23386268", "access_depth": "full_text_partial", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Methods:paragraph1, 1:Methods:paragraph4, 3:Discussion:paragraph8, 3:Discussion:paragraph9, 3:Discussion:paragraph10, 3:Discussion:paragraph18, 3:Discussion:paragraph21. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "contradicts", "what_it_shows": "Recovered Sydney trial data show greater mortality under the linoleic-acid replacement intervention.", "what_it_does_not_show": "Primary participant-data reanalysis only; original protocol and precise trans-fat exposure unavailable, and linked erratum details not examined.", "confounders_present": [ "Primary participant-data reanalysis only; original protocol and precise trans-fat exposure unavailable, and linked erratum details not examined." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [] }, { "n": 49, "pmid": "29897866", "title": "Primary Prevention of Cardiovascular Disease with a Mediterranean Diet Supplemented with Extra-Virgin Olive Oil or Nuts.", "citation": "Estruch R, Ros E, Salas-Salvadó J et al. Primary Prevention of Cardiovascular Disease with a Mediterranean Diet Supplemented with Extra-Virgin Olive Oil or Nuts. The New England journal of medicine. 2018.", "doi": "10.1056/NEJMoa1800389", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/29897866/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29897866/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID29897866", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Corrected PREDIMED analysis retains lower cardiovascular events for olive-oil/nut Mediterranean diets.", "what_it_does_not_show": "Allocation departures and adjusted reanalysis; multifactor diet versus reduced-fat advice does not isolate the nominal exchange.", "confounders_present": [ "Allocation departures and adjusted reanalysis; multifactor diet versus reduced-fat advice does not isolate the nominal exchange." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [] }, { "n": 50, "pmid": "27071971", "title": "Re-evaluation of the traditional diet-heart hypothesis: analysis of recovered data from Minnesota Coronary Experiment (1968-73).", "citation": "Ramsden CE, Zamora D, Majchrzak-Hong S et al. Re-evaluation of the traditional diet-heart hypothesis: analysis of recovered data from Minnesota Coronary Experiment (1968-73). BMJ (Clinical research ed.). 2016.", "doi": "10.1136/bmj.i1246", "pmcid": "PMC4836695", "url": "https://pubmed.ncbi.nlm.nih.gov/27071971/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27071971/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID38942429" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "MINNESOTA", "access_depth": "full_text_partial", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Methods:paragraph6, 1:Methods:paragraph9, 2:Results:paragraph8. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "null", "what_it_shows": "Recovered Minnesota trial data confirm cholesterol lowering without mortality benefit.", "what_it_does_not_show": "Primary trial reanalysis only; incomplete raw recovery and inpatient exposure. The 2024 correction repairs a thesis link, not results.", "confounders_present": [ "Primary trial reanalysis only; incomplete raw recovery and inpatient exposure. The 2024 correction repairs a thesis link, not results." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": true, "provider": "Scite", "retrieved_on": "2026-10-11", "tally": { "total": 342, "supporting": 11, "contrasting": 1, "mentioning": 316, "citingPublications": 375 }, "notable_contrasting_statements": [], "note": "Provider tally only. Returned snippets are outgoing references from this anchor, not incoming contrasting evidence. No grade inferred from counts; editorial notices were not returned." }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [] }, { "n": 51, "pmid": "26016869", "title": "Replacement of saturated with unsaturated fats had no impact on vascular function but beneficial effects on lipid biomarkers, E-selectin, and blood pressure: results from the randomized, controlled Dietary Intervention and VAScular function (DIVAS) study.", "citation": "Vafeiadou K, Weech M, Altowaijri H et al. Replacement of saturated with unsaturated fats had no impact on vascular function but beneficial effects on lipid biomarkers, E-selectin, and blood pressure: results from the randomized, controlled Dietary Intervention and VAScular function (DIVAS) study. The American journal of clinical nutrition. 2015.", "doi": "10.3945/ajcn.114.097089", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/26016869/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26016869/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID26016869", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "Randomized isoenergetic DIVAS replacement reduces LDL but not its primary vascular-function endpoint.", "what_it_does_not_show": "Estimated mortality reduction is modeled from lipid change, not observed deaths; short duration.", "confounders_present": [ "Estimated mortality reduction is modeled from lipid change, not observed deaths; short duration." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 52, "pmid": "39111551", "title": "Variation of LDL cholesterol in response to the replacement of saturated with unsaturated fatty acids: a nonrandomized, sequential dietary intervention; the Reading, Imperial, Surrey, Saturated fat Cholesterol Intervention (\"RISSCI\"-1) study.", "citation": "Koutsos A, Griffin BA, Antoni R et al. Variation of LDL cholesterol in response to the replacement of saturated with unsaturated fatty acids: a nonrandomized, sequential dietary intervention; the Reading, Imperial, Surrey, Saturated fat Cholesterol Intervention (\"RISSCI\"-1) study. The American journal of clinical nutrition. 2024.", "doi": "10.1016/j.ajcnut.2024.07.032", "pmcid": "PMC11473524", "url": "https://pubmed.ncbi.nlm.nih.gov/39111551/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39111551/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "RISSCI", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "RISSCI-1 sequential exchange lowers average LDL/apoB with marked individual variation.", "what_it_does_not_show": "Nonrandomized fixed sequence and biomarker outcomes; the original design must not be called an RCT.", "confounders_present": [ "Nonrandomized fixed sequence and biomarker outcomes; the original design must not be called an RCT." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 53, "pmid": "42664559", "title": "Impact of saturated fat absorption on serum low density lipoprotein-cholesterol response to the replacement of saturated with unsaturated fats in healthy males. The 'Reading, Imperial, Surrey, Saturated fat Cholesterol Intervention-2 (RISSCI-2)' non-randomised sequential dietary intervention study.", "citation": "Fielding BA, Koutsos A, Antoni R et al. Impact of saturated fat absorption on serum low density lipoprotein-cholesterol response to the replacement of saturated with unsaturated fats in healthy males. The 'Reading, Imperial, Surrey, Saturated fat Cholesterol Intervention-2 (RISSCI-2)' non-randomised sequential dietary intervention study. Atherosclerosis. 2026.", "doi": "10.1016/j.atherosclerosis.2026.121884", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/42664559/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/42664559/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "RISSCI", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "RISSCI-2 repeats response variation and finds absorption does not explain the high/low-response contrast.", "what_it_does_not_show": "Participants selected by prior response; shared screening cohort and exploratory mechanism cannot redefine nominal scope.", "confounders_present": [ "Participants selected by prior response; shared screening cohort and exploratory mechanism cannot redefine nominal scope." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] } ], "verification_summary": { "load_bearing_claims_checked": 57, "verified": 57, "unverified": 0, "contradicted": 0, "note": "Verified attribution is distinct from mechanism truth or complete body access." }, "factual_issues_found": [], "cap_rules_applied": [ { "subclaim_id": "SC1", "cap": "Γ", "cap_source": "universal", "triggered": true, "trigger_text_quoted": "Biomarker change without functional/phenotypic change caps at Γ.", "specific_trigger": "Controlled feeding demonstrates a real biochemical LDL/apoB response, with heterogeneous responses across food matrices and comparators. The isolated SC1 evidence has biomarker endpoints, so the aging rubric functional-phenotype ceiling is Γ; this letter does not deny causality of the measured lipid response.", "resulting_ceiling": "Γ" } ], "cap_precedence_resolutions": [ { "collision": "Perturbation in a defined setting versus broader inference", "subclaim_scope_cap_binds_on": "Replacing cis-unsaturated dietary fats with saturated fats causally increases ASCVD risk through elevation of LDL/apoB particles.", "subclaim_scope_threshold_binds_on": "The precise experimentally tested subclaim scope", "resolution": "The biomarker-only cap binds isolated SC1 and dietary LDL-only evidence offered as direct event proof. It is not reapplied to the complementary human genetic plus randomized clinical SC2 set. SC3 uses that set with clinical dietary intervention and substitution evidence; it cannot inherit Η wholesale because diet-specific net effects and selective mediation retain shared confounders. Carbohydrate and trans-fat comparisons do not silently replace the registered cis-unsaturated comparator.", "note": "Convergent lines are assessed as a set; one weak leg is not re-capped over the assembled case." } ], "boundary_check_BGD": [ { "subclaim_id": "SC1", "field_valid_perturbation_quote": "\n- Genetic or pharmacologic intervention producing reproducible lifespan/healthspan extension\n- Must separate developmental effects from true aging effects\n- Biomarker change alone does NOT satisfy this threshold", "qualifying_evidence_present": "no", "qualifying_evidence_citation": "", "gamma_hard_rules_triggered": [ "Abstract association, cellular rescue and biomarker response alone do not demonstrate the registered human clinical claim.", "Positive narrow perturbations retain their scope; null studies do not earn positive threshold crossings." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "Controlled feeding demonstrates a real biochemical LDL/apoB response, with heterogeneous responses across food matrices and comparators. The isolated SC1 evidence has biomarker endpoints, so the aging rubric functional-phenotype ceiling is Γ; this letter does not deny causality of the measured lipid response.", "ceiling_from_boundary_check": "Γ" }, { "subclaim_id": "SC2", "field_valid_perturbation_quote": "\n- Genetic or pharmacologic intervention producing reproducible lifespan/healthspan extension\n- Must separate developmental effects from true aging effects\n- Biomarker change alone does NOT satisfy this threshold", "qualifying_evidence_present": "yes", "qualifying_evidence_citation": "PMID32203549, PMID30694319, PMID28304224, PMID30403574, PMID41211925", "gamma_hard_rules_triggered": [ "Abstract association, cellular rescue and biomarker response alone do not demonstrate the registered human clinical claim.", "Positive narrow perturbations retain their scope; null studies do not earn positive threshold crossings." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "yes", "perturbation_result_note": "Randomized clinical particle-lowering, human causal genetics and lifelong hypercholesterolemia converge on apoB-particle contribution to ASCVD. Different genotypes, drug strategies and clinical settings constrain distinct errors. Dietary trial conflicts do not overturn this independently supported causal component.", "ceiling_from_boundary_check": "Δ or higher" }, { "subclaim_id": "SC3", "field_valid_perturbation_quote": "\n- Genetic or pharmacologic intervention producing reproducible lifespan/healthspan extension\n- Must separate developmental effects from true aging effects\n- Biomarker change alone does NOT satisfy this threshold", "qualifying_evidence_present": "yes", "qualifying_evidence_citation": "PMID393644, PMID3511692, PMID30694319, PMID28304224, PMID29897866", "gamma_hard_rules_triggered": [ "Abstract association, cellular rescue and biomarker response alone do not demonstrate the registered human clinical claim.", "Positive narrow perturbations retain their scope; null studies do not earn positive threshold crossings." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "yes", "perturbation_result_note": "The assembled replacement, particle-causal and clinical-dietary evidence supports context-specific particle-mediated risk. It is stronger than biomarkers alone when read as a complementary causal set, but direct diet-specific clinical mediation, universal food-class effects and equally supported MUFA/PUFA event benefits remain unresolved. Clinical dietary patterns and historical replacements map restricted context rather than a universal guaranteed outcome.", "ceiling_from_boundary_check": "Δ or higher" } ], "thresholds_tested": [ { "subclaim_id": "SC1", "threshold": "Δ", "requirement_quoted": "Requires at least one intervention changing lifespan or healthspan in a way consistent with the hypothesis.", "satisfied": "no", "supporting_evidence": [], "what_would_cross_it": "Functional clinical outcomes linked to the measured particle change are required to exceed its isolated biomarker ceiling; the complementary SC2 set supplies that broader clinical link." }, { "subclaim_id": "SC2", "threshold": "Δ", "requirement_quoted": "Requires at least one intervention changing lifespan or healthspan in a way consistent with the hypothesis.", "satisfied": "yes", "supporting_evidence": [ "[14] Multivariable MR prioritizes apoB for CHD over correlated lipid measures.", "[16] LPL and LDLR genetic scores yield similar lower CHD risk per apoB decrement despite differing cholesterol/triglyceride effects.", "[25] Randomized evolocumab reduces LDL and major cardiovascular events on statin background.", "[26] Randomized alirocumab reduces clinical events after acute coronary syndrome.", "[27] Evolocumab reduces first cardiovascular-event composites in selected high-risk patients without prior MI/stroke." ], "what_would_cross_it": "" }, { "subclaim_id": "SC2", "threshold": "Ε", "requirement_quoted": "Requires causal effect in constrained contexts, backgrounds, or species.", "satisfied": "yes", "supporting_evidence": [ "[14] Multivariable MR prioritizes apoB for CHD over correlated lipid measures.", "[16] LPL and LDLR genetic scores yield similar lower CHD risk per apoB decrement despite differing cholesterol/triglyceride effects.", "[25] Randomized evolocumab reduces LDL and major cardiovascular events on statin background.", "[26] Randomized alirocumab reduces clinical events after acute coronary syndrome.", "[27] Evolocumab reduces first cardiovascular-event composites in selected high-risk patients without prior MI/stroke." ], "what_would_cross_it": "" }, { "subclaim_id": "SC2", "threshold": "Ζ", "requirement_quoted": "Requires:\n- Reproducible intervention effects\n- Mechanistic narrowing\n- Evidence not reducible to general sickness, caloric reduction, or developmental artifacts", "satisfied": "yes", "supporting_evidence": [ "[14] Multivariable MR prioritizes apoB for CHD over correlated lipid measures.", "[16] LPL and LDLR genetic scores yield similar lower CHD risk per apoB decrement despite differing cholesterol/triglyceride effects.", "[25] Randomized evolocumab reduces LDL and major cardiovascular events on statin background.", "[26] Randomized alirocumab reduces clinical events after acute coronary syndrome.", "[27] Evolocumab reduces first cardiovascular-event composites in selected high-risk patients without prior MI/stroke." ], "what_would_cross_it": "" }, { "subclaim_id": "SC2", "threshold": "Η", "requirement_quoted": "Requires:\n- Robust cross-context intervention evidence\n- Mechanistic specificity\n- Strong alignment of lifespan/healthspan outcomes", "satisfied": "yes", "supporting_evidence": [ "[14] Multivariable MR prioritizes apoB for CHD over correlated lipid measures.", "[16] LPL and LDLR genetic scores yield similar lower CHD risk per apoB decrement despite differing cholesterol/triglyceride effects.", "[25] Randomized evolocumab reduces LDL and major cardiovascular events on statin background.", "[26] Randomized alirocumab reduces clinical events after acute coronary syndrome.", "[27] Evolocumab reduces first cardiovascular-event composites in selected high-risk patients without prior MI/stroke." ], "what_would_cross_it": "" }, { "subclaim_id": "SC2", "threshold": "Θ", "requirement_quoted": "Requires high reproducibility with minimal contextual contradiction.", "satisfied": "no", "supporting_evidence": [ "[14] Multivariable MR prioritizes apoB for CHD over correlated lipid measures.", "[16] LPL and LDLR genetic scores yield similar lower CHD risk per apoB decrement despite differing cholesterol/triglyceride effects.", "[25] Randomized evolocumab reduces LDL and major cardiovascular events on statin background.", "[26] Randomized alirocumab reduces clinical events after acute coronary syndrome.", "[27] Evolocumab reduces first cardiovascular-event composites in selected high-risk patients without prior MI/stroke." ], "what_would_cross_it": "Further independent selective perturbation with prespecified particle-mediated clinical prediction, stable applicability across risk/ancestry and explicit residual-risk accounting would support Θ; neither universal necessity nor sufficiency is shown." }, { "subclaim_id": "SC3", "threshold": "Δ", "requirement_quoted": "Requires at least one intervention changing lifespan or healthspan in a way consistent with the hypothesis.", "satisfied": "yes", "supporting_evidence": [ "[2] Finnish hospital diet periods with lower saturated fat/cholesterol show lower serum cholesterol and coronary incidence.", "[6] Oslo diet/antismoking intervention retains lower coronary-event rates on follow-up.", "[16] LPL and LDLR genetic scores yield similar lower CHD risk per apoB decrement despite differing cholesterol/triglyceride effects.", "[25] Randomized evolocumab reduces LDL and major cardiovascular events on statin background.", "[49] Corrected PREDIMED analysis retains lower cardiovascular events for olive-oil/nut Mediterranean diets." ], "what_would_cross_it": "" }, { "subclaim_id": "SC3", "threshold": "Ε", "requirement_quoted": "Requires causal effect in constrained contexts, backgrounds, or species.", "satisfied": "yes", "supporting_evidence": [ "[2] Finnish hospital diet periods with lower saturated fat/cholesterol show lower serum cholesterol and coronary incidence.", "[6] Oslo diet/antismoking intervention retains lower coronary-event rates on follow-up.", "[16] LPL and LDLR genetic scores yield similar lower CHD risk per apoB decrement despite differing cholesterol/triglyceride effects.", "[25] Randomized evolocumab reduces LDL and major cardiovascular events on statin background.", "[49] Corrected PREDIMED analysis retains lower cardiovascular events for olive-oil/nut Mediterranean diets." ], "what_would_cross_it": "" }, { "subclaim_id": "SC3", "threshold": "Ζ", "requirement_quoted": "Requires:\n- Reproducible intervention effects\n- Mechanistic narrowing\n- Evidence not reducible to general sickness, caloric reduction, or developmental artifacts", "satisfied": "no", "supporting_evidence": [ "[2] Finnish hospital diet periods with lower saturated fat/cholesterol show lower serum cholesterol and coronary incidence.", "[6] Oslo diet/antismoking intervention retains lower coronary-event rates on follow-up.", "[16] LPL and LDLR genetic scores yield similar lower CHD risk per apoB decrement despite differing cholesterol/triglyceride effects.", "[25] Randomized evolocumab reduces LDL and major cardiovascular events on statin background.", "[49] Corrected PREDIMED analysis retains lower cardiovascular events for olive-oil/nut Mediterranean diets." ], "what_would_cross_it": "A well-controlled long-term isoenergetic SFA-for-cis-UFA trial, specified fatty-acid species and food matrices, verified sustained apoB separation and adjudicated ASCVD events, with independent replication and prespecified mediation, would narrow major alternatives sufficiently for Ζ." } ], "generalization_check": { "generalization_tested": "yes", "context_boundary_mapped": "yes", "internal_negative_controls": [ "Minnesota lowers cholesterol without clinical/mortality benefit; original report and recovered analysis share one trial.", "Sydney linoleic-acid intervention has unfavorable mortality, with precise trans-fat composition unresolved.", "DIVAS primary vascular-function endpoint is null despite secondary lipid improvement.", "Coconut/olive and palm/cocoa-butter trials limit uniform SFA-class lipid responses." ], "note": "Baseline metabolic state, fatty-acid species, cis-PUFA versus cis-MUFA, food matrix and duration map positive context boundaries. Carb replacement and multicomponent diet benefits address different contrasts. This is context-specific risk contribution, not universal mortality benefit." }, "falsification_patterns_met": [ { "pattern": "Biomarker improvement without the proposed clinical benefit", "evidence": "Minnesota and DIVAS retain null clinical/vascular endpoints despite cholesterol lowering; effects constrain universality without re-capping independent SC2.", "downgrade_applied": false } ], "pitfalls_flagged": [ { "pitfall": "Primary clinical mediation inferred from a lipid-only endpoint", "where": "SC1 and short feeding studies; DIVAS projected mortality." }, { "pitfall": "Wrong replacement comparator", "where": "Carbohydrate, trans-fat and multicomponent-diet results do not equal fixed cis-UFA exchange." }, { "pitfall": "Shared cohort reports counted as independent causal lines", "where": "FOURIER, STRIP, Minnesota, RISSCI and repeated GWAS resources." } ], "causal_tally_audit": { "tally_claimed_by_document": 8, "tally_after_audit": 8, "tally_unit": "Positive qualifying study units across scoped subclaims, not independent causal lines or full-claim necessity/sufficiency.", "screened_discriminating_contrasts": 37, "items_rejected": [ "Null and negative contrasts are discriminators, not positive threshold crossings. Reports and replications are not independent causal lines.", "Reports sharing recruitment, instruments or randomization are not automatically independent causal lines.", "The tally includes discriminating contrasts; positive qualifying source lists alone determine threshold crossings." ] }, "steelman": { "case_one_rung_higher": "One rung above, Ζ: randomized feeding, natural genetics, drug clinical outcomes and multiple diet programs are orthogonal. Together they warrant causal risk expectation. However, independent same-scope selective dietary clinical mediation is not established across matrices and both cis-UFA classes; endpoint conflicts and shared historical-trial limitations leave major alternatives open.", "case_one_rung_lower": "One rung below, Δ: only a first contribution has been shown and direct selective feeding-event proof is weak. Yet the biochemical-to-clinical chain has independent human causal support, multiple clinical dietary contexts and mapped comparator boundaries. Ε better represents causal operation with constrained generalization, while the assignment remains less secure than SC2.", "which_rejected": "Retain Ε for assembled SC3; reject automatic transfer to Ζ and reject biomarker-only Γ as a description of the entire complementary clinical causal set.", "blocking_cap_threshold_or_missing_experiment": "Missing experiment: Independently run, preregistered long-term isoenergetic replacement trial with fixed SFA species, cis-PUFA/cis-MUFA comparators, matched food matrices, trans-fat measurement, sustained apoB separation and blinded adjudicated ASCVD outcomes; prospectively test mediation and competing metabolic pathways." }, "final_score": { "hsef_level": "Ε", "hsef_descriptor": "Context-specific causality established", "confidence": "Moderate", "confidence_rationale": "53 primary reports with 4 selected partial-body examinations; density, heterogeneous controls and incomplete access set the confidence, not correctness.", "rests_on_non_peer_reviewed_work": false, "rationale": "Overall Ε follows preregistered SC3. The isolated biomarker component is Γ and the independently convergent particle-to-ASCVD component is Η. SC3 is assessed on their assembled complementary evidence with clinical dietary results, not by reimposing the biomarker cap on the whole set. Comparator-specific effects, historical endpoint conflicts, food matrix and uncertain selective mediation prevent broad diet-specific Ζ. This remains a bounded reviewer judgement, not a numerical estimate of individual risk." }, "role_of_mechanism": { "classification": "reinforcing / stabilizing factor", "derivation_step_matched": 5, "derivation": "Dietary exposure changes lipids and clinical risk, so it is not solely a downstream marker or co-occurrence. Replacing this exposure neither prevents all ASCVD nor has proven universal initiating/rate-limiting status; familial, metabolic and other risks persist. It is not universally required. Step 5 assigns a modifiable amplifier of atherosclerotic risk, not a sole primary cause.", "tournament_used_as_tiebreaker": false, "note": "Derived from causal direction, not tournament rank." }, "extended_scoring_MSD": { "momentum": { "value": "Mechanistic only", "artifact": "RISSCI-2 (PMID42664559, 2026) tests absorption as a response mechanism and does not find it explains the high/low-response contrast. VESALIUS-CV (PMID41211925) extends clinical particle lowering to a different risk population. Neither is a new selective dietary mediation trial crossing SC3 to Ζ.", "justification": "RISSCI-2 (PMID42664559, 2026) tests absorption as a response mechanism and does not find it explains the high/low-response contrast. VESALIUS-CV (PMID41211925) extends clinical particle lowering to a different risk population. Neither is a new selective dietary mediation trial crossing SC3 to Ζ." }, "stability": { "value": "Stable", "trigger": "No verified named pending result that would change the registered full-scope grade was identified. This does not mean that no relevant trial exists.", "justification": "No verified named pending result that would change the registered full-scope grade was identified. This does not mean that no relevant trial exists." }, "divergence": { "implied_level": null, "implied_level_basis": "No single field-implied level is defensible from conflicting framings.", "assessed_level": "Ε", "gap_in_rungs": null, "value": "Contested", "justification": "No manufactured field consensus or arithmetic gap." }, "calibration_note": "M/S/D never modify HSEF level or confidence." }, "change_record": { "applies": false, "prior_level": "none assigned", "prior_confidence": null, "prior_source": null, "derived_before_consulting_prior": true, "new_level": "Ε", "direction": "newly assigned", "what_moved_it": "Fresh primary evidence appraisal; not blinded.", "divergence_from_other_reviewers": null }, "proposed_decisive_experiments": [ { "name": "Registered boundary experiment", "experiment": "Independently run, preregistered long-term isoenergetic replacement trial with fixed SFA species, cis-PUFA/cis-MUFA comparators, matched food matrices, trans-fat measurement, sustained apoB separation and blinded adjudicated ASCVD outcomes; prospectively test mediation and competing metabolic pathways.", "readout": "Adjudicated ASCVD events and prespecified exposure/apoB-mediated risk differences", "critical_control": "Energy balance, food matrix, adherence, medications, cis/trans composition, unbiased allocation and outcome assessment", "supporting_result": "Replicated clinical event separation aligned with sustained particle differences under the specified replacement", "falsifying_result": "Adequate sustained exposure and apoB separation with precise absent or opposite event effect, or benefits explained by prespecified nonparticle pathways" } ], "knowledge_gaps": [ { "name": "Gap 1", "statement": "Selective diet-specific clinical mediation remains weaker than particle causality.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 2", "statement": "Cis-MUFA and cis-PUFA, individual SFA species and food matrices need separate effect estimates.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 3", "statement": "Historical trans-fat exposure and incomplete data recovery remain unresolved; contamination must not be asserted as an established explanation of nulls.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 4", "statement": "Mean response and responder-defined follow-up are distinct populations.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 5", "statement": "More diverse clinical populations and complete correction/supplement checks are needed.", "relevance": "Limits mechanism identification or scope." } ], "review_metadata": { "review_date": "2026-10-11", "reviewer": "Codex", "evidence_base_note": "53 primary reports; literature cutoff 2026-10-09; source examination UTC date 2026-10-12; bounded critical review, not exhaustive systematic review.", "literature_tools_available": true, "literature_tools_note": "Life Sciences Literature PubMed/Entrez, separately logged public original-body retrieval, and Consensus Pro browser searches. Provider output retained as observed browser text with citation-link mappings, or as previously exported connector documents where present. AI synthesis is not primary full-text verification. Consensus retrieved/included counts are not examined-primary counts. One Scite call covered five anchors: provider tallies and outgoing reference contexts, not audited incoming contrasting statements. One SciSpace discovery call returned supplementary leads; none added to the primary count. No independent blinded review.", "skill_version": "5.3", "validator_run": "PASS: exact archived HSEF v5.3 validator, rerun after final sealing.", "validator_warnings_addressed": "No warnings.", "limits": "Bounded critical review; not an exhaustive systematic review, complete-paper audit, independent scientific peer review or blinded calibration. HIV is an existing draft carried forward after a source checkpoint." }, "is_calibration_entry": { "value": false, "entry_role": "not_calibration", "blind_graded": null, "completed_blinded_calibration": false, "expected_band_sealed_at": "", "target_sha256": "", "target_authorship": "not applicable", "target_author_saw_review": null, "future_run_status": "not prepared", "unblinded_reason": "Ranking categorical verdict and index guidance were visible. No completed blinded calibration claimed." }, "upper_ladder_check": { "final_level_below_zeta": true, "equivalents_considered": [ { "kind": "mendelian_randomization", "available": true, "why_not_sufficient": "Human MR, lifelong exposure and randomized clinical perturbation support Η for SC2 despite individual observational weaknesses. Shared UK Biobank/GWAS and PCSK9 class dependencies are retained. SC3 lacks equally independent, selective diet-specific clinical mediation across predetermined replacements and matrices; this scope gap prevents Ζ without downgrading the independent particle causal set." }, { "kind": "natural_experiment", "available": true, "why_not_sufficient": "Human MR, lifelong exposure and randomized clinical perturbation support Η for SC2 despite individual observational weaknesses. Shared UK Biobank/GWAS and PCSK9 class dependencies are retained. SC3 lacks equally independent, selective diet-specific clinical mediation across predetermined replacements and matrices; this scope gap prevents Ζ without downgrading the independent particle causal set." }, { "kind": "dose_response_across_populations", "available": false, "why_not_sufficient": "Human MR, lifelong exposure and randomized clinical perturbation support Η for SC2 despite individual observational weaknesses. Shared UK Biobank/GWAS and PCSK9 class dependencies are retained. SC3 lacks equally independent, selective diet-specific clinical mediation across predetermined replacements and matrices; this scope gap prevents Ζ without downgrading the independent particle causal set." }, { "kind": "withdrawal_rechallenge", "available": false, "why_not_sufficient": "Human MR, lifelong exposure and randomized clinical perturbation support Η for SC2 despite individual observational weaknesses. Shared UK Biobank/GWAS and PCSK9 class dependencies are retained. SC3 lacks equally independent, selective diet-specific clinical mediation across predetermined replacements and matrices; this scope gap prevents Ζ without downgrading the independent particle causal set." }, { "kind": "therapeutic_perturbation_hard_endpoint", "available": false, "why_not_sufficient": "Human MR, lifelong exposure and randomized clinical perturbation support Η for SC2 despite individual observational weaknesses. Shared UK Biobank/GWAS and PCSK9 class dependencies are retained. SC3 lacks equally independent, selective diet-specific clinical mediation across predetermined replacements and matrices; this scope gap prevents Ζ without downgrading the independent particle causal set." } ], "convergence_present": true, "cap_reapplied_to_convergent_set": false }, "provenance_header": { "sources_total": 53, "claims_total": 57, "claims_verified": 57, "claims_unverified": 0, "claims_contradicted": 0, "tier_a_sources": 53, "generated_by": "Codex; HSEF v5.3", "gate_passed": true }, "claims": [ { "id": "C1", "text": "Achieving STRIP dietary targets associates with better aortic structure and distensibility. Target attainment is not randomized; shared parent cohort and surrogate vascular outcomes.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 1 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C2", "text": "Finnish hospital diet periods with lower saturated fat/cholesterol show lower serum cholesterol and coronary incidence. Hospital-period crossover, changing admissions and multifactor diet prevent clean individual randomization or selective fat mediation.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 2 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C3", "text": "STRIP target achievement associates with improved lipids and insulin sensitivity. Postrandomization adherence comparison; shares recruitment with PMID32209700 and changes fibre too.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 3 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C4", "text": "Three replacement diets lower LDL in a small domiciliary feeding study. Very small sample; multiple macronutrient changes and no coronary endpoints.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 4 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C5", "text": "LCPUFA and Nordic diets reduce LDL and liver fat versus usual care in metabolic disease. Ad-libitum dietary patterns and differing weight changes; no selective saturated-fat clinical-outcome attribution.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 5 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C6", "text": "Oslo diet/antismoking intervention retains lower coronary-event rates on follow-up. Diet and smoking were changed together; clinical benefit is not exclusively saturated-fat replacement.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 6 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C7", "text": "Ketogenic high-fat feeding raises LDL and apoB in young normal-weight women. Carbohydrate, total fat and fatty-acid composition all change; incomplete retention and short duration.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 7 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C8", "text": "High-saturated-fat low-carbohydrate feeding improves selected lipid traits without an LDL increase versus comparators. Carbohydrate replacement differs from fixed cis-unsaturated replacement; linked correction details not examined.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 8 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C9", "text": "Palm/cocoa-butter and olive-oil diets have similar tested lipid responses in young participants. Fatty-acid positioning and limited sample/time constrain universal fat-class predictions.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 9 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C10", "text": "Cohort substitution models associate replacing SFA with PUFA/MUFA with lower CHD risk. Diet-reporting, residual confounding and overlapping US cohorts; modeled exchange is not randomized.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 10 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C11", "text": "Dairy-fat substitution risk differs by replacement nutrient; PUFA replacement associates with lower CVD. Dairy versus carbohydrate is not the nominal comparison; overlaps US cohort resources.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 11 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C12", "text": "Meat-versus-dairy SFA substitution associates with different coronary risk. Observational food-matrix differences and residual confounding; cannot isolate fatty acids alone.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 12 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C13", "text": "Long-term Norwegian data associate higher SFA intake with mortality and model benefit of replacement. Measurement error, secular changes and residual confounding; theoretical exchange is not an intervention.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 13 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C14", "text": "Multivariable MR prioritizes apoB for CHD over correlated lipid measures. Instrument validity, collinearity and shared GWAS restrict exclusive mediation interpretation.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 14 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 2:Results:paragraph7. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C15", "text": "Agnostic multivariable genetic analysis consistently prioritizes apoB for coronary disease. Shared genetic resources and instrument assumptions; not an independent dietary experiment.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 15 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C16", "text": "LPL and LDLR genetic scores yield similar lower CHD risk per apoB decrement despite differing cholesterol/triglyceride effects. Lifelong genetic exposure and pleiotropy; does not estimate a food-substitution treatment effect.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 16 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C17", "text": "Genetically predicted apoB and LDL associate with coronary disease and mortality across dose ranges. Selection and nonlinear-MR assumptions; triglyceride pleiotropy and overlapping resources remain.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 17 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C18", "text": "Liver-fat genetic clusters show coronary-risk directions aligning with apoB changes. Statistical mediation and pleiotropy cannot establish all biological pathways or dietary specificity.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 18 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C19", "text": "Genetic analysis estimates greater CHD atherogenicity per Lp(a)-apoB particle than LDL-apoB. Particle types are not interchangeable; assumptions and populations constrain the magnitude estimate.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 19 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C20", "text": "Remnant-associated genetic clusters show greater coronary-risk effects per apoB than LDL-associated clusters. Shared UK Biobank and differing pathways; not all apoB particles have equal risk weights.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 20 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C21", "text": "APOC3 and LDL-lowering genetic variants show additive CHD associations aligned with apoB. Drug-target genetic proxies are lifelong and partly pleiotropic; not randomized therapy or diet.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 21 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C22", "text": "FOURIER extension shows durable low LDL and lower events by original treatment allocation. Selected open-label extension with both groups treated; not a new independent randomization.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 22 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C23", "text": "RACING combination therapy is clinically noninferior to intensive statin with more LDL target attainment. Active-active noninferiority does not show benefit against untreated exposure or prove exclusive apoB mediation.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 23 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C24", "text": "FOURIER achieved-LDL analysis shows a monotonic relation with later events. Achieved LDL is not randomized; shared parent randomization and selection after baseline.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 24 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C25", "text": "Randomized evolocumab reduces LDL and major cardiovascular events on statin background. Drug strategy rather than diet; limited duration and residual risk preclude universal necessity/sufficiency.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 25 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C26", "text": "Randomized alirocumab reduces clinical events after acute coronary syndrome. PCSK9 drug class shares mechanistic vulnerabilities with evolocumab; not direct SFA exchange.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 26 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C27", "text": "Evolocumab reduces first cardiovascular-event composites in selected high-risk patients without prior MI/stroke. High-risk disease/diabetes eligibility and mostly White participants; not universal primary prevention or a feeding trial.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 27 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C28", "text": "GLAGOV LDL lowering reduces coronary plaque volume and increases regression. Imaging phenotype is not clinical-event benefit; mechanistic support complements event trials.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 28 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C29", "text": "Monogenic and polygenic hypercholesterolemia associate with higher ASCVD risk even at comparable measured LDL. Lifetime exposure differs from single measurement; selected genotype groups and linked erratum require caution.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 29 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C30", "text": "FH variant severity tracks LDL patterns with substantial within-variant variation. Selected familial clinical sample; not a general-population diet intervention or sole causal line.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 30 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C31", "text": "Lower achieved LDL in FOURIER-OLE associates with fewer subsequent clinical events. Postrandomization exposure, extension selection and shared cohort; not independent randomized dose assignment.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 31 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C32", "text": "Minnesota dietary replacement lowers cholesterol without overall cardiovascular or mortality benefit. Limited inpatient exposure, dietary cholesterol changes and historical food composition; shares trial with PMID27071971.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 32 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C33", "text": "Lyon Mediterranean dietary pattern retains lower recurrent cardiovascular complications. Multicomponent dietary pattern and secondary prevention; no selective saturated-fat/apoB mediation test.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 33 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C34", "text": "Matched weight gain under SFA versus PUFA overfeeding produces different liver/visceral fat accumulation. Excess-calorie metabolic experiment, not ordinary-energy coronary-event replacement.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 34 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C35", "text": "Different plant cooking oils alter membrane composition without significant between-group lipid changes. All comparators are plant oils; no direct saturated-versus-cis-unsaturated contrast or clinical endpoints.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 35 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C36", "text": "Low-SFA egg-containing feeding lowers LDL versus high-SFA control, with particle-subfraction changes. Eggs and fat composition change together; linked erratum not examined and no measured event reduction.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 36 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C37", "text": "PURE associates higher fat intake with lower total mortality and no clear MI/CVD-mortality association. Carbohydrate comparison and socioeconomic/energy confounding differ from fixed cis-unsaturated replacement.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 37 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C38", "text": "UK Biobank macronutrient associations are nonlinear and depend on intake range. Diet assessment and residual confounding; correction details not examined and cohort overlaps genetic analyses.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 38 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C39", "text": "Cashew feeding lowers LDL relative to a potato-chip snack comparator. Carbohydrate/food-matrix replacement, not selective SFA exchange; short-term biomarkers.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 39 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C40", "text": "Controlled safflower/salmon diets show lipid and apoB changes differing between normal and FCHL participants. Genotype and n-3/n-6 effects vary; no coronary endpoints or universal response.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 40 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C41", "text": "Mediterranean lifestyle program improves glycemic control and quality of life with nonsignificant lipid patterns. Multicomponent lifestyle intervention cannot isolate dietary fat or particle-mediated ASCVD prevention.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 41 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C42", "text": "SCRIP multifactor intervention shows a borderline lesion-level reduction and nonsignificant patient-level new-lesion difference. Multiple risk-factor treatments and correlated vessel segments; dietary correlation is not randomized mediation.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 42 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C43", "text": "Weight-maintaining high-fibre vegetable/fruit/nut diet lowers LDL and changes fecal steroid loss. Small short feeding study; fibre and food matrix prevent SFA-specific attribution or clinical-event inference.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 43 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C44", "text": "Dietary cholesterol response differs by baseline cholesterol after accounting for regression toward the mean. Responsiveness analysis is not a selective randomized SFA comparison or clinical endpoint test.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 44 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C45", "text": "Butter raises LDL relative to olive/coconut oils; coconut and olive responses do not differ significantly. Free-living addition or substitution, short duration and different SFA species; no clinical events.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 45 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Methods:paragraph2, 1:Methods:paragraph3. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C46", "text": "Canola/safflower diets reduce LDL and apoB versus initial American-diet baseline. Small sample and baseline-to-intervention order; not clinical-outcome evidence.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 46 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C47", "text": "Avocado-rich MUFA replacement for carbohydrate improves selected lipids in diabetes. Carbohydrate comparator and food matrix differ from the fixed SFA replacement question.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 47 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C48", "text": "Recovered Sydney trial data show greater mortality under the linoleic-acid replacement intervention. Primary participant-data reanalysis only; original protocol and precise trans-fat exposure unavailable, and linked erratum details not examined.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 48 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Methods:paragraph1, 1:Methods:paragraph4, 3:Discussion:paragraph8, 3:Discussion:paragraph9, 3:Discussion:paragraph10, 3:Discussion:paragraph18, 3:Discussion:paragraph21. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C49", "text": "Corrected PREDIMED analysis retains lower cardiovascular events for olive-oil/nut Mediterranean diets. Allocation departures and adjusted reanalysis; multifactor diet versus reduced-fat advice does not isolate the nominal exchange.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 49 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C50", "text": "Recovered Minnesota trial data confirm cholesterol lowering without mortality benefit. Primary trial reanalysis only; incomplete raw recovery and inpatient exposure. The 2024 correction repairs a thesis link, not results.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 50 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Methods:paragraph6, 1:Methods:paragraph9, 2:Results:paragraph8. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C51", "text": "Randomized isoenergetic DIVAS replacement reduces LDL but not its primary vascular-function endpoint. Estimated mortality reduction is modeled from lipid change, not observed deaths; short duration.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 51 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C52", "text": "RISSCI-1 sequential exchange lowers average LDL/apoB with marked individual variation. Nonrandomized fixed sequence and biomarker outcomes; the original design must not be called an RCT.", "carries_number": true, "load_bearing_for": [ "SC1" ], "source_ns": [ 52 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C53", "text": "RISSCI-2 repeats response variation and finds absorption does not explain the high/low-response contrast. Participants selected by prior response; shared screening cohort and exploratory mechanism cannot redefine nominal scope.", "carries_number": true, "load_bearing_for": [ "SC1" ], "source_ns": [ 53 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "CSC1", "text": "Controlled feeding demonstrates a real biochemical LDL/apoB response, with heterogeneous responses across food matrices and comparators. The isolated SC1 evidence has biomarker endpoints, so the aging rubric functional-phenotype ceiling is Γ; this letter does not deny causality of the measured lipid response.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 1, 2, 3, 4, 5, 7, 8, 9, 32, 34, 35, 36, 39, 40, 43, 44, 45, 46, 47, 48, 50, 51, 52, 53 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-12", "note": "" }, { "id": "CSC2", "text": "Randomized clinical particle-lowering, human causal genetics and lifelong hypercholesterolemia converge on apoB-particle contribution to ASCVD. Different genotypes, drug strategies and clinical settings constrain distinct errors. Dietary trial conflicts do not overturn this independently supported causal component.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-12", "note": "" }, { "id": "CSC3", "text": "The assembled replacement, particle-causal and clinical-dietary evidence supports context-specific particle-mediated risk. It is stronger than biomarkers alone when read as a complementary causal set, but direct diet-specific clinical mediation, universal food-class effects and equally supported MUFA/PUFA event benefits remain unresolved. Clinical dietary patterns and historical replacements map restricted context rather than a universal guaranteed outcome.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 1, 2, 6, 10, 11, 12, 13, 32, 33, 37, 38, 41, 42, 48, 49, 50, 51 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-12", "note": "" }, { "id": "CH", "text": "Saturated-for-cis-unsaturated replacement can raise LDL/apoB and is expected to raise ASCVD risk; the net clinical effect depends on the replacement, food matrix and exposure context.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 51, 52, 25, 16, 50, 48 ], "verification": "verified", "verified_against": "Bounded synthesis of examined sources; score is adjudication.", "verified_on": "2026-10-12", "note": "" } ], "citation_ledger": [ { "n": 1, "citation": "Laitinen TT, Nuotio J, Rovio SP et al. Dietary Fats and Atherosclerosis From Childhood to Adulthood. Pediatrics. 2020.", "tier": "A", "kind": "rct", "pmid": "32209700", "doi": "10.1542/peds.2019-2786", "url": "https://pubmed.ncbi.nlm.nih.gov/32209700/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "STRIP", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C1", "CSC1", "CSC3" ] }, { "n": 2, "citation": "Turpeinen O, Karvonen MJ, Pekkarinen M et al. Dietary prevention of coronary heart disease: the Finnish Mental Hospital Study. International journal of epidemiology. 1979.", "tier": "A", "kind": "rct", "pmid": "393644", "doi": "10.1093/ije/8.2.99", "url": "https://pubmed.ncbi.nlm.nih.gov/393644/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID393644", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C2", "CSC1", "CSC3" ] }, { "n": 3, "citation": "Laitinen TT, Nuotio J, Juonala M et al. Success in Achieving the Targets of the 20-Year Infancy-Onset Dietary Intervention: Association With Insulin Sensitivity and Serum Lipids. Diabetes care. 2018.", "tier": "A", "kind": "rct", "pmid": "30072407", "doi": "10.2337/dc18-0869", "url": "https://pubmed.ncbi.nlm.nih.gov/30072407/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "STRIP", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C3", "CSC1" ] }, { "n": 4, "citation": "Grundy SM, Nix D, Whelan MF et al. Comparison of three cholesterol-lowering diets in normolipidemic men. 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Nutrients. 2021.", "tier": "A", "kind": "rct", "pmid": "33801247", "doi": "10.3390/nu13030814", "url": "https://pubmed.ncbi.nlm.nih.gov/33801247/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID33801247", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C7", "CSC1" ] }, { "n": 8, "citation": "Ebbeling CB, Knapp A, Johnson A et al. Effects of a low-carbohydrate diet on insulin-resistant dyslipoproteinemia-a randomized controlled feeding trial. The American journal of clinical nutrition. 2022.", "tier": "A", "kind": "rct", "pmid": "34582545", "doi": "10.1093/ajcn/nqab287", "url": "https://pubmed.ncbi.nlm.nih.gov/34582545/", "status_flags": [ "ErratumIn: PMID35022668" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID34582545", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C8", "CSC1" ] }, { "n": 9, "citation": "Stonehouse W, Benassi-Evans B, James-Martin G et al. Fatty acid regio-specificity of triacylglycerol molecules may affect plasma lipid responses to dietary fats-a randomised controlled cross-over trial. European journal of clinical nutrition. 2020.", "tier": "A", "kind": "rct", "pmid": "31227804", "doi": "10.1038/s41430-019-0452-7", "url": "https://pubmed.ncbi.nlm.nih.gov/31227804/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID31227804", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C9", "CSC1" ] }, { "n": 10, "citation": "Li Y, Hruby A, Bernstein AM et al. Saturated Fats Compared With Unsaturated Fats and Sources of Carbohydrates in Relation to Risk of Coronary Heart Disease: A Prospective Cohort Study. Journal of the American College of Cardiology. 2015.", "tier": "A", "kind": "primary", "pmid": "26429077", "doi": "10.1016/j.jacc.2015.07.055", "url": "https://pubmed.ncbi.nlm.nih.gov/26429077/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID26429077", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C10", "CSC3" ] }, { "n": 11, "citation": "Chen M, Li Y, Sun Q et al. Dairy fat and risk of cardiovascular disease in 3 cohorts of US adults. The American journal of clinical nutrition. 2016.", "tier": "A", "kind": "primary", "pmid": "27557656", "doi": "10.3945/ajcn.116.134460", "url": "https://pubmed.ncbi.nlm.nih.gov/27557656/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID27557656", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C11", "CSC3" ] }, { "n": 12, "citation": "Vissers LET, Rijksen J, Boer JMA et al. Fatty acids from dairy and meat and their association with risk of coronary heart disease. European journal of nutrition. 2019.", "tier": "A", "kind": "primary", "pmid": "30167851", "doi": "10.1007/s00394-018-1811-1", "url": "https://pubmed.ncbi.nlm.nih.gov/30167851/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID30167851", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C12", "CSC3" ] }, { "n": 13, "citation": "Arnesen EK, Laake I, Veierød MB et al. Saturated fatty acids and total and CVD mortality in Norway: a prospective cohort study with up to 45 years of follow-up. The British journal of nutrition. 2024.", "tier": "A", "kind": "primary", "pmid": "39279644", "doi": "10.1017/S0007114524001351", "url": "https://pubmed.ncbi.nlm.nih.gov/39279644/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID39279644", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C13", "CSC3" ] }, { "n": 14, "citation": "Richardson TG, Sanderson E, Palmer TM et al. Evaluating the relationship between circulating lipoprotein lipids and apolipoproteins with risk of coronary heart disease: A multivariable Mendelian randomisation analysis. PLoS medicine. 2020.", "tier": "A", "kind": "primary", "pmid": "32203549", "doi": "10.1371/journal.pmed.1003062", "url": "https://pubmed.ncbi.nlm.nih.gov/32203549/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID32203549", "access_depth": "full_text_partial", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 2:Results:paragraph7. No complete-paper or supplement audit claimed.", "carries_claims": [ "C14", "CSC2" ] }, { "n": 15, "citation": "Zuber V, Gill D, Ala-Korpela M et al. High-throughput multivariable Mendelian randomization analysis prioritizes apolipoprotein B as key lipid risk factor for coronary artery disease. International journal of epidemiology. 2021.", "tier": "A", "kind": "primary", "pmid": "33130851", "doi": "10.1093/ije/dyaa216", "url": "https://pubmed.ncbi.nlm.nih.gov/33130851/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID33130851", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C15", "CSC2" ] }, { "n": 16, "citation": "Ference BA, Kastelein JJP, Ray KK et al. Association of Triglyceride-Lowering LPL Variants and LDL-C-Lowering LDLR Variants With Risk of Coronary Heart Disease. JAMA. 2019.", "tier": "A", "kind": "primary", "pmid": "30694319", "doi": "10.1001/jama.2018.20045", "url": "https://pubmed.ncbi.nlm.nih.gov/30694319/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID30694319", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C16", "CSC2", "CH" ] }, { "n": 17, "citation": "Yang G, Mason AM, Wood AM et al. Dose-Response Associations of Lipid Traits With Coronary Artery Disease and Mortality. JAMA network open. 2024.", "tier": "A", "kind": "primary", "pmid": "38241044", "doi": "10.1001/jamanetworkopen.2023.52572", "url": "https://pubmed.ncbi.nlm.nih.gov/38241044/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID38241044", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C17", "CSC2" ] }, { "n": 18, "citation": "Björnson E, Adiels M, Bergström G et al. The relationship between genetic liver fat and coronary heart disease is explained by apoB-containing lipoproteins. Atherosclerosis. 2024.", "tier": "A", "kind": "primary", "pmid": "38102060", "doi": "10.1016/j.atherosclerosis.2023.117397", "url": "https://pubmed.ncbi.nlm.nih.gov/38102060/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID38102060", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C18", "CSC2" ] }, { "n": 19, "citation": "Björnson E, Adiels M, Taskinen MR et al. Lipoprotein(a) Is Markedly More Atherogenic Than LDL: An Apolipoprotein B-Based Genetic Analysis. 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Diabetes care. 1994.", "tier": "A", "kind": "rct", "pmid": "8026287", "doi": "10.2337/diacare.17.4.311", "url": "https://pubmed.ncbi.nlm.nih.gov/8026287/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID8026287", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C47", "CSC1" ] }, { "n": 48, "citation": "Ramsden CE, Zamora D, Leelarthaepin B et al. Use of dietary linoleic acid for secondary prevention of coronary heart disease and death: evaluation of recovered data from the Sydney Diet Heart Study and updated meta-analysis. 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Primary Prevention of Cardiovascular Disease with a Mediterranean Diet Supplemented with Extra-Virgin Olive Oil or Nuts. The New England journal of medicine. 2018.", "tier": "A", "kind": "primary", "pmid": "29897866", "doi": "10.1056/NEJMoa1800389", "url": "https://pubmed.ncbi.nlm.nih.gov/29897866/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID29897866", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C49", "CSC3" ] }, { "n": 50, "citation": "Ramsden CE, Zamora D, Majchrzak-Hong S et al. Re-evaluation of the traditional diet-heart hypothesis: analysis of recovered data from Minnesota Coronary Experiment (1968-73). BMJ (Clinical research ed.). 2016.", "tier": "A", "kind": "primary", "pmid": "27071971", "doi": "10.1136/bmj.i1246", "url": "https://pubmed.ncbi.nlm.nih.gov/27071971/", "status_flags": [ "ErratumIn: PMID38942429" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "MINNESOTA", "access_depth": "full_text_partial", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Methods:paragraph6, 1:Methods:paragraph9, 2:Results:paragraph8. No complete-paper or supplement audit claimed.", "carries_claims": [ "C50", "CSC1", "CSC3", "CH" ] }, { "n": 51, "citation": "Vafeiadou K, Weech M, Altowaijri H et al. Replacement of saturated with unsaturated fats had no impact on vascular function but beneficial effects on lipid biomarkers, E-selectin, and blood pressure: results from the randomized, controlled Dietary Intervention and VAScular function (DIVAS) study. The American journal of clinical nutrition. 2015.", "tier": "A", "kind": "rct", "pmid": "26016869", "doi": "10.3945/ajcn.114.097089", "url": "https://pubmed.ncbi.nlm.nih.gov/26016869/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID26016869", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C51", "CSC1", "CSC3", "CH" ] }, { "n": 52, "citation": "Koutsos A, Griffin BA, Antoni R et al. Variation of LDL cholesterol in response to the replacement of saturated with unsaturated fatty acids: a nonrandomized, sequential dietary intervention; the Reading, Imperial, Surrey, Saturated fat Cholesterol Intervention (\"RISSCI\"-1) study. The American journal of clinical nutrition. 2024.", "tier": "A", "kind": "primary", "pmid": "39111551", "doi": "10.1016/j.ajcnut.2024.07.032", "url": "https://pubmed.ncbi.nlm.nih.gov/39111551/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "RISSCI", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C52", "CSC1", "CH" ] }, { "n": 53, "citation": "Fielding BA, Koutsos A, Antoni R et al. Impact of saturated fat absorption on serum low density lipoprotein-cholesterol response to the replacement of saturated with unsaturated fats in healthy males. The 'Reading, Imperial, Surrey, Saturated fat Cholesterol Intervention-2 (RISSCI-2)' non-randomised sequential dietary intervention study. Atherosclerosis. 2026.", "tier": "A", "kind": "primary", "pmid": "42664559", "doi": "10.1016/j.atherosclerosis.2026.121884", "url": "https://pubmed.ncbi.nlm.nih.gov/42664559/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "RISSCI", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C53", "CSC1" ] } ], "independence_basis": { "required": true, "lines": [ { "label": "Controlled dietary exposure", "sources": [ 51, 45, 40 ], "excludes_error": "Constrains nutrient-reporting and treatment-selection error, but trials are short and food changes can be pleiotropic." }, { "label": "Inherited particle-pathway contrasts", "sources": [ 16, 14, 29 ], "excludes_error": "Constrains reverse clinical causation and short-term adherence; pleiotropy, selection and shared cohorts remain." }, { "label": "Randomized clinical particle lowering", "sources": [ 25, 26, 27 ], "excludes_error": "Constrains allocation and outcome confounding, with measured LDL and clinical events; related drug classes share off-target assumptions." }, { "label": "Clinical dietary interventions", "sources": [ 2, 50, 48, 49 ], "excludes_error": "Measures clinical net effects directly, but matrix, adherence, allocation/recovery and multiple nutrients constrain selective attribution." } ], "shared_failure_mode_checked": true, "note": "FOURIER and its achieved-LDL/extension reports share randomization or selected follow-up; they are one program, not four independent trials. Minnesota reanalyses share the original cohort. STRIP and RISSCI follow-ups share participants. US nutrition cohorts and UK Biobank/GWAS resources share dietary measurement or genetic assumptions. Genetics, feeding and clinical drug trials constrain different errors; none proves all dietary net effects alone." }, "consensus_validation": { "completed": true, "status": "completed_original_source_reconciliation", "provider_mode": "Consensus Pro signed-in browser; observed response and citation-link mappings", "queries": [ "https://consensus.app/search/diet-heart-hypothesis-saturated-fats/wjKdkYXTQA-v0nXfwPcBVQ/" ], "query_record_note": "Observed thread URL and visible request/response in raw receipt; no unobserved query payload reconstructed.", "primary_comparison_count": 5, "primary_comparisons": [ { "pmid": "26016869", "doi": "10.3945/ajcn.114.097089", "source_type": "primary study report", "study_group": "PMID26016869", "access_depth": "abstract_metadata", "consensus_aspect": "Replacing saturated fat changes lipids and vascular risk.", "result_comparison": "Original DIVAS abstract reports beneficial lipid changes but a null primary vascular-function comparison. A projected mortality reduction is a risk calculation, not observed trial deaths.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/26016869/", "source_examination_receipts": [ "deliverables\\hsef_v53_remaining_priority_06_10_2026-10-09\\lipid-heart-diet\\examinations\\resumption-50-53-5000.json" ], "body_receipts": [] }, { "pmid": "39111551", "doi": "10.1016/j.ajcnut.2024.07.032", "source_type": "primary study report", "study_group": "RISSCI", "access_depth": "abstract_metadata", "consensus_aspect": "RISSCI informs individual dietary lipid responses.", "result_comparison": "Original primary abstract describes a nonrandomized sequential dietary design. Average LDL/apoB reduction is informative but does not become a randomized event-endpoint trial.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/39111551/", "source_examination_receipts": [ "deliverables\\hsef_v53_remaining_priority_06_10_2026-10-09\\lipid-heart-diet\\examinations\\resumption-50-53-5000.json" ], "body_receipts": [] }, { "pmid": "42664559", "doi": "10.1016/j.atherosclerosis.2026.121884", "source_type": "primary study report", "study_group": "RISSCI", "access_depth": "abstract_metadata", "consensus_aspect": "Recent follow-up informs mechanisms of variable response.", "result_comparison": "Original RISSCI-2 abstract uses participants selected on prior response and does not establish absorption as the explanation. It is not an independent population replication of RISSCI-1.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/42664559/", "source_examination_receipts": [ "deliverables\\hsef_v53_remaining_priority_06_10_2026-10-09\\lipid-heart-diet\\examinations\\resumption-50-53-5000.json" ], "body_receipts": [] }, { "pmid": "27071971", "doi": "10.1136/bmj.i1246", "source_type": "primary study report", "study_group": "MINNESOTA", "access_depth": "full_text_partial", "consensus_aspect": "Historical dietary trials limit a universal benefit claim.", "result_comparison": "Original Minnesota reanalysis body separates cholesterol lowering from its clinical mortality result and incomplete historical follow-up. The linked 2024 correction repairs a thesis link; it does not reverse the results.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/27071971/", "source_examination_receipts": [ "deliverables\\hsef_v53_remaining_priority_06_10_2026-10-09\\lipid-heart-diet\\examinations\\resumption-34-50-1300.json" ], "body_receipts": [ "deliverables\\hsef_v53_remaining_priority_06_10_2026-10-09\\lipid-heart-diet\\body-presentation-receipts\\27071971-s1-p6-9.json", "deliverables\\hsef_v53_remaining_priority_06_10_2026-10-09\\lipid-heart-diet\\body-presentation-receipts\\27071971-s2-p8.json" ] }, { "pmid": "23386268", "doi": "10.1136/bmj.e8707", "source_type": "primary study report", "study_group": "PMID23386268", "access_depth": "full_text_partial", "consensus_aspect": "Dietary nulls/adverse findings require methodological context.", "result_comparison": "Original Sydney body reports unmeasured trans-fat exposure and other dietary uncertainties. They cannot be discarded as proven trans-fat contamination.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/23386268/", "source_examination_receipts": [ "deliverables\\hsef_v53_remaining_priority_06_10_2026-10-09\\lipid-heart-diet\\examinations\\resumption-34-50-1300.json" ], "body_receipts": [ "deliverables\\hsef_v53_remaining_priority_06_10_2026-10-09\\lipid-heart-diet\\body-presentation-receipts\\23386268-s1-p1-4.json", "deliverables\\hsef_v53_remaining_priority_06_10_2026-10-09\\lipid-heart-diet\\body-presentation-receipts\\23386268-s3-p8-9-10-18-21.json" ] } ], "grade_changed": false, "grade_change_note": "Comparison does not introduce an independently blinded regrade; bounded case adjudication remains source-based.", "raw_receipts": [ { "path": "deliverables\\hsef_v53_remaining_priority_06_10_2026-10-09\\lipid-heart-diet\\consensus-browser-2026-10-11.json", "sha256": "6d51a80ea3ab221641d596d1152dfb285c57ec02ebce6a7c093dbc75bd6fd6bd" } ], "independent_blinded_audit": false, "cutoff": "2026-10-09", "completed_utc": "2026-10-12T02:11:33.104277+00:00", "conclusion": "Specific qualifiers and endpoint hierarchy above are retained in the evidence cards; AI wording does not override the original sources." } }