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Cited by 404Fatty Acid Research and HealthNutritional Studies and DietAquaculture Nutrition and Growth

ω-3 Polyunsaturated Fatty Acid Biomarkers and Coronary Heart Disease: Pooling Project of 19 Cohort Studies

Open access
Del Gobbo, Liana C., Imamura, Fumiaki, Aslibekyan, Stella, Marklund, Matti, Virtanen, Jyrki K., Wennberg, Maria, Yakoob, Mohammad Y., Chiuve, Stephanie E. +42 more·2016·JAMA Internal Medicine
DOI 10.1001/jamainternmed.2016.2925PMC PMC5183535
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Abstract

IMPORTANCE: The role of ω-3 polyunsaturated fatty acids for primary prevention of coronary heart disease (CHD) remains controversial. Most prior longitudinal studies evaluated self-reported consumption rather than biomarkers. OBJECTIVE: To evaluate biomarkers of seafood-derived eicosapentaenoic acid (EPA; 20:5ω-3), docosapentaenoic acid (DPA; 22:5ω-3), and docosahexaenoic acid (DHA; 22:6ω-3) and plant-derived α-linolenic acid (ALA; 18:3ω-3) for incident CHD. DATA SOURCES: A global consortium of 19 studies identified by November 2014. STUDY SELECTION: Available prospective (cohort, nested case-control) or retrospective studies with circulating or tissue ω-3 biomarkers and ascertained CHD. DATA EXTRACTION AND SYNTHESIS: Each study conducted standardized, individual-level analysis using harmonized models, exposures, outcomes, and covariates. Findings were centrally pooled using random-effects meta-analysis. Heterogeneity was examined by age, sex, race, diabetes, statins, aspirin, ω-6 levels, and FADS desaturase genes. MAIN OUTCOMES AND MEASURES: Incident total CHD, fatal CHD, and nonfatal myocardial infarction (MI). RESULTS: The 19 studies comprised 16 countries, 45 637 unique individuals, and 7973 total CHD, 2781 fatal CHD, and 7157 nonfatal MI events, with ω-3 measures in total plasma, phospholipids, cholesterol esters, and adipose tissue. Median age at baseline was 59 years (range, 18-97 years), and 28 660 (62.8%) were male. In continuous (per 1-SD increase) multivariable-adjusted analyses, the ω-3 biomarkers ALA, DPA, and DHA were associated with a lower risk of fatal CHD, with relative risks (RRs) of 0.91 (95% CI, 0.84-0.98) for ALA, 0.90 (95% CI, 0.85-0.96) for DPA, and 0.90 (95% CI, 0.84-0.96) for DHA. Although DPA was associated with a lower risk of total CHD (RR, 0.94; 95% CI, 0.90-0.99), ALA (RR, 1.00; 95% CI, 0.95-1.05), EPA (RR, 0.94; 95% CI, 0.87-1.02), and DHA (RR, 0.95; 95% CI, 0.91-1.00) were not. Significant associations with nonfatal MI were not evident. Associations appeared generally stronger in phospholipids and total plasma. Restricted cubic splines did not identify evidence of nonlinearity in dose responses. CONCLUSIONS AND RELEVANCE: On the basis of available studies of free-living populations globally, biomarker concentrations of seafood and plant-derived ω-3 fatty acids are associated with a modestly lower incidence of fatal CHD.

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Crossref · 10.1001/jamainternmed.2016.2925

Cites

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Statistics

Nothing to recompute.

Claims the paper makes

0 of 72 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    In quintile analyses, DHA was linked to lower fatal CHD risk (quintile 5 vs 1: RR 0.77, 95% CI 0.64-0.89).

    “and DHA (RR, 0.77; 95% CI, 0.64–0.89)”
    Quote in the paperSubstantial claim
  • Findingown data

    In quintile analyses, DPA was linked to lower fatal CHD risk (quintile 5 vs 1: RR 0.76, 95% CI 0.65-0.90).

    “lower risk of fatal CHD was evident with DPA (RR, 0.76; 95% CI, 0.65–0.90)”
    Quote in the paperSubstantial claim
  • Findingown data

    Compared with white individuals, ALA was linked to a significantly lower nonfatal MI risk among African American individuals (P for heterogeneity = .001).

    “Compared with white individuals, ALA was associated with a significantly lower risk of nonfatal MI among African American individuals (P for heterogeneity = .001).”
    Quote in the paperNot a substantial claim
  • Findingown data

    No significant interaction was found with FADS desaturase gene variants.

    “no significant interaction was identified by FADS desaturase gene variants”
    Quote in the paperNot a substantial claim
  • Findingown data

    In continuous multivariable-adjusted models, higher DHA biomarker levels were linked to lower fatal CHD risk (RR 0.90, 95% CI 0.84-0.96).

    “0.90 (95% CI, 0.84–0.96) for DHA”
    Quote in the paperSubstantial claim
  • May combine two claims. 28
  • Classified as probably not a substantial claim. 14

  • May combine two claims.

    Findingown data

    Associations of ω-3 PUFA biomarkers with incident CHD did not differ significantly by age, sex, ω-6 PUFA levels, type 2 diabetes, statin use, regular aspirin use, year of biomarker sampling, or (for ALA) EPA, DPA, and DHA levels.

    “No significant differences in associations of ω-3 PUFA biomarkers with incident CHD events were observed by age, sex, ω-6 PUFA (LA or AA) concentrations, type 2 diabetes status, statin use, regular aspirin use, year of biomarker sampling, or (for ALA) EPA, DPA, and DHA concentrations (P for heterogeneity >.05 for each)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The 19 included studies came from 16 countries and comprised 45,637 unique individuals, with 7,973 total CHD events, 2,781 fatal CHD events, and 7,157 nonfatal MI events; ω-3 measures were from total plasma, phospholipids, cholesterol esters, and adipose tissue.

    “The 19 studies comprised 16 countries, 45 637 unique individuals, and 7973 total CHD, 2781 fatal CHD, and 7157 nonfatal MI events, with ω-3 measures in total plasma, phospholipids, cholesterol esters, and adipose tissue.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    Median age at baseline was 59 years (range 18-97), and 28,660 participants (62.8%) were male.

    “Median age at baseline was 59 years (range, 18–97 years), and 28 660 (62.8%) were male.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    No appreciable differences appeared after excluding early cases (first 2 years), censoring at 6 years, excluding retrospective studies, or excluding studies with self-reported events.

    “Compared with the main findings, no appreciable differences were observed after excluding cases identified in the first 2 years after biomarker sampling, censoring participants at the first 6 years of follow-up, excluding retrospective studies, or excluding studies with self-reported events”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Across biomarker types, inverse associations were generally stronger in phospholipid and total plasma compartments, and heterogeneity fell when adipose tissue and cholesterol ester estimates were excluded.

    “Across biomarker types, inverse associations were generally stronger in the phospholipid and total plasma compartments (Table 2); heterogeneity decreased when adipose tissue and cholesterol ester estimates were excluded from meta-analyses.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Across the included studies, findings were consistent by age, sex, ω-6 PUFA LA and AA levels, year of biomarker sampling, diabetes status, statin use, and aspirin use.

    “Across these diverse studies, findings were consistent by age, sex, ω-6 PUFA LA and AA levels, year of biomarker sampling, presence or absence of diabetes, statin use, and aspirin use.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The findings suggest generally stronger inverse associations with CHD for EPA, DPA, and DHA in phospholipids and total plasma, although fewer estimates and cases were available for adipose and cholesterol esters compartments, decreasing precision.

    “Our findings suggest generally stronger inverse associations with CHD for EPA, DPA, and DHA in phospholipids and total plasma, although fewer estimates and cases were available for adipose and cholesterol esters compartments, decreasing precision.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Compared with prior work, this study had a far larger number of events, including more than a 4-fold larger number for fatal CHD.

    “Compared with priorwork,42 we also took advantage of a far larger number of events (eg, >4-fold larger for fatal CHD)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [42] Chowdhury R Warnakula S Kunutsor S Association of dietary, circulating, and supplement fatty acids with coronary risk: a systematic review and meta-analysis Ann Intern Med 2014 160 6 398 406 24723079 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Most prior research has focused on seafood-derived long-chain ω-3 PUFAs, and the potential CHD effects of plant-derived ALA are far less understood.

    “most prior research11 has focused on seafood-derived long-chain ω-3 PUFAs, and potential CHD effects of plant-derived α-linolenic acid (ALA; 18:3ω-3) are far less understood.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [11] Pan A Chen M Chowdhury R α-Linolenic acid and risk of cardiovascular disease: a systematic review and meta-analysis Am J Clin Nutr 2012 96 6 1262 1273 23076616 PMC3497923 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Most of those trials gave supplements for a few years or less and enrolled patients with existing CHD or at high CHD risk who were taking multiple cardiovascular drugs.

    “most trials provided supplements for a few years or less and were conducted in patients with preexisting CHD or at high risk for CHD and taking multiple cardiovascular drugs.”
    Quote in the paperSubstantial claim0 of 7 sources checked
    • cites [2] Bucher HC Hengstler P Schindler C Meier G N-3 polyunsaturated fatty acids in coronary heart disease: a meta-analysis of randomized controlled trials Am J Med 2002 112 4 298 304 11893369 source

      Not checked in the free run.

    • cites [3] Hooper L Thompson RL Harrison RA Omega 3 fatty acids for prevention and treatment of cardiovascular disease Cochrane Database Syst Rev 2004 4 CD003177 15495044 PMC4170890 source

      Not checked in the free run.

    • cites [4] León H Shibata MC Sivakumaran S Dorgan M Chatterley T Tsuyuki RT Effect of fish oil on arrhythmias and mortality: systematic review BMJ 2008 337 a2931 10.1136/bmj.a2931 19106137 PMC2612582 source

      Not checked in the free run.

    • cites [5] Marik PE Varon J Omega-3 dietary supplements and the risk of cardiovascular events: a systematic review Clin Cardiol 2009 32 7 365 372 19609891 PMC6653319 source

      Not checked in the free run.

    • cites [6] Trikalinos TA Lee J Moorthy D Effects of Eicosapentanoic Acid and Docosahexanoic Acid on Mortality Across Diverse Settings: Systematic Review and Meta-analysis of Randomized Trials and Prospective Cohorts Rockville, MD Agency for Healthcare Research and Quality 2012 22479722

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [7] Kwak SM Myung SK Lee YJ Seo HG Korean Meta-analysis Study Group Efficacy of ω-3 fatty acid supplements (eicosapentaenoic acid and docosahexaenoic acid) in the secondary prevention of cardiovascular disease: a meta-analysis of randomized, double-blind, placebo-controlled trials Arch Intern Med 2012 172 9 686 694 22493407 source

      Not checked in the free run.

    • cites [8] Rizos EC Ntzani EE Bika E Kostapanos MS Elisaf MS Association between ω-3 fatty acid supplementation and risk of major cardiovascular disease events: a systematic review and meta-analysis JAMA 2012 308 10 1024 1033 22968891 source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    A handful of studies have measured objective circulating or tissue ω-3 PUFA levels, but such findings could be limited by publication bias.

    “A previous review1 also found that a handful of studies have measured objective circulating or tissue ω-3 PUFA levels, but such findings could be limited by publication bias.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] Mozaffarian D Wu JHY Omega-3 fatty acids and cardiovascular disease: effects on risk factors, molecular pathways, and clinical events J Am Coll Cardiol 2011 58 20 2047 2067 22051327 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In those trials, background dietary intake was usually not measured, and many participants may have already had adequate intake from diet.

    “the background dietary intake in these trials was not usually measured, and many participants may have had adequate intake from diet alone.”
    Quote in the paperSubstantial claim0 of 7 sources checked
    • cites [2] Bucher HC Hengstler P Schindler C Meier G N-3 polyunsaturated fatty acids in coronary heart disease: a meta-analysis of randomized controlled trials Am J Med 2002 112 4 298 304 11893369 source

      Not checked in the free run.

    • cites [3] Hooper L Thompson RL Harrison RA Omega 3 fatty acids for prevention and treatment of cardiovascular disease Cochrane Database Syst Rev 2004 4 CD003177 15495044 PMC4170890 source

      Not checked in the free run.

    • cites [4] León H Shibata MC Sivakumaran S Dorgan M Chatterley T Tsuyuki RT Effect of fish oil on arrhythmias and mortality: systematic review BMJ 2008 337 a2931 10.1136/bmj.a2931 19106137 PMC2612582 source

      Not checked in the free run.

    • cites [5] Marik PE Varon J Omega-3 dietary supplements and the risk of cardiovascular events: a systematic review Clin Cardiol 2009 32 7 365 372 19609891 PMC6653319 source

      Not checked in the free run.

    • cites [6] Trikalinos TA Lee J Moorthy D Effects of Eicosapentanoic Acid and Docosahexanoic Acid on Mortality Across Diverse Settings: Systematic Review and Meta-analysis of Randomized Trials and Prospective Cohorts Rockville, MD Agency for Healthcare Research and Quality 2012 22479722

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [7] Kwak SM Myung SK Lee YJ Seo HG Korean Meta-analysis Study Group Efficacy of ω-3 fatty acid supplements (eicosapentaenoic acid and docosahexaenoic acid) in the secondary prevention of cardiovascular disease: a meta-analysis of randomized, double-blind, placebo-controlled trials Arch Intern Med 2012 172 9 686 694 22493407 source

      Not checked in the free run.

    • cites [8] Rizos EC Ntzani EE Bika E Kostapanos MS Elisaf MS Association between ω-3 fatty acid supplementation and risk of major cardiovascular disease events: a systematic review and meta-analysis JAMA 2012 308 10 1024 1033 22968891 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Prespecified subgroup heterogeneity was assessed by pooling study-specific results within defined strata.

    “Heterogeneity by prespecified subgroups was evaluated by pooling individual study results based on defined strata”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    Soft CHD end points (e.g., angina, revascularization) were excluded to reduce ascertainment bias.

    “We excluded soft CHD end points (eg, angina, revascularization) to minimize bias in ascertainment of these events.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    For most fatty acids and biomarkers, coefficients of variation were below 10%.

    “with coefficients of variation less than 10% for most fatty acids and biomarkers”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In randomized clinical trials, long-chain ω-3 PUFAs benefit multiple major cardiovascular risk factors, including triglyceride levels, blood pressure, heart rate, heart rate variability, endothelial function, and myocardial oxygen demand.

    “In randomized clinical trials, long-chain ω-3 PUFAs benefit multiple major cardiovascular risk factors, including triglyceride levels, blood pressure, heart rate, heart rate variability, endothelial function, and myocardial oxygen demand.1,10”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [1] Mozaffarian D Wu JHY Omega-3 fatty acids and cardiovascular disease: effects on risk factors, molecular pathways, and clinical events J Am Coll Cardiol 2011 58 20 2047 2067 22051327 source

      Not checked in the free run.

    • cites [10] Mozaffarian D Wu JH (n-3) fatty acids and cardiovascular health: are effects of EPA and DHA shared or complementary? J Nutr 2012 142 3 614S 625S 22279134 PMC3278271 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Several sensitivity analyses were performed.

    “Several sensitivity analyses were performed.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    The paper's findings are consistent with prior experimental evidence that long-chain ω-3 PUFAs may stabilize membranes in ischemia-induced ventricular fibrillation and with observational evidence that fish consumption benefits relate most to arrhythmic events and fatal CHD.

    “Our findings are consistent with prior experimental evidence that long-chain ω-3 PUFAs may have membrane stabilizing actions in the setting of ischemia-induced ventricular fibrillation1,38 and observational evidence indicating that benefits of fish consumption are most related to arrhythmic events39 and fatal CHD.40”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [1] Mozaffarian D Wu JHY Omega-3 fatty acids and cardiovascular disease: effects on risk factors, molecular pathways, and clinical events J Am Coll Cardiol 2011 58 20 2047 2067 22051327 source

      Not checked in the free run.

    • cites [38] Siscovick DS Lemaitre RN Mozaffarian D The fish story: a diet-heart hypothesis with clinical implications: n-3 polyunsaturated fatty acids, myocardial vulnerability, and sudden death Circulation 2003 107 21 2632 2634 12782612 source

      Not checked in the free run.

    • cites [39] Siscovick DS Raghunathan TE King I Dietary intake and cell membrane levels of long-chain n-3 polyunsaturated fatty acids and the risk of primary cardiac arrest JAMA 1995 274 17 1363 1367 7563561 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Covariates were standardized across studies using prespecified, harmonized definitions and categorizations.

    “Covariates were standardized across studies based on prespecified, harmonized definitions and categorizations”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A previous study suggests DPA may inhibit ex vivo collagen-stimulated platelet aggregation, thromboxane production, and cyclooxygenase 1 activity.

    “a previous study10 suggests that DPA may inhibit ex vivo collagen-stimulated platelet aggregation, thromboxane production, and cyclooxygenase 1 activity.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Mozaffarian D Wu JH (n-3) fatty acids and cardiovascular health: are effects of EPA and DHA shared or complementary? J Nutr 2012 142 3 614S 625S 22279134 PMC3278271 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The prespecified primary analysis used inverse-variance weights.

    “Our prespecified primary analysis used inverse-variance weights.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    A standardized analysis protocol with harmonized definitions of populations, exposures, outcomes, covariates, effect modifiers, and pooling methods was developed and given to each participating study.

    “A standardized analysis protocol was developed and provided to each participating study, including harmonized definitions of populations, exposures, outcomes, covariates, effect modifiers, and methods for pooling across studies.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    A key strength of the analysis was a prespecified, harmonized analytic plan using individual-level data within each study, which allowed consistent assessment of how ALA relates to CHD.

    “A key strength of our analysis was the prespecified, harmonized analytic plan using individual-level data within each study, which allowed consistent assessment of how ALA relates to CHD.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The results support use of phospholipids or total plasma for long-chain ω-3 PUFA exposure and a need for further investigation of optimal biomarkers for assessing ALA.

    “Our results support use of phospholipids or total plasma for long-chain ω-3 PUFA exposure and a need for further investigation of optimal biomarkers for assessing ALA.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductcitation

    Few studies were available with African American (n = 2) and Chinese (n = 2) subgroups.

    “few studies were available with African American (n = 2 studies: CHS and MESA) and Chinese subgroups (n = 2 studies: SCHS and MESA).27,33”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [27] Bild DE Bluemke DA Burke GL Multi-Ethnic Study of Atherosclerosis: objectives and design Am J Epidemiol 2002 156 9 871 881 12397006 source

      Not checked in the free run.

    • cites [33] Hankin JH Stram DO Arakawa K Singapore Chinese Health Study: development, validation, and calibration of the quantitative food frequency questionnaire Nutr Cancer 2001 39 2 187 195 11759279 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Randomized clinical trials of fish oil supplements have found mixed effects, but overall pooled findings indicate a benefit in lowering risk of cardiac death.

    “Randomized clinical trials of fish oil supplements have found mixed effects, although overall pooled findings indicate a benefit in lowering risk of cardiac death,8 consistent with our findings.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Rizos EC Ntzani EE Bika E Kostapanos MS Elisaf MS Association between ω-3 fatty acid supplementation and risk of major cardiovascular disease events: a systematic review and meta-analysis JAMA 2012 308 10 1024 1033 22968891 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Because the findings reflect habitual ω-3 exposure for primary CHD prevention, they do not imply that fish oil supplementation will necessarily reduce CHD events, particularly with short-term treatment or preexisting CHD.

    “Because our findings reflect habitual ω-3 exposure for primary CHD prevention, our results do not imply that fish oil supplementation will necessarily reduce CHD events, particularly in the context of short-term treatment or in those with preexisting CHD.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Baseline ω-3 PUFA biomarker concentrations reflect habitual dietary intake over the relevant etiologic period.

  • May combine two claims.

    Study design and conductreasoning

    All cohorts assessed ω-3 PUFA exposure once at baseline, and changes over time would attenuate findings toward the null, causing underestimation of associations.

    “All cohorts assessed ω-3 PUFA exposure once at baseline, and changes over time would attenuate findings toward the null, causing underestimation of associations.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductreasoning

    Because the analysis used observational studies, biomarkers and risk factors were not evenly distributed by randomization; unmeasured or residual confounding cannot be excluded, and ω-3 biomarker measures may in part be markers of a long-term healthy lifestyle.

    “Because we analyzed observational studies, biomarkers and risk factors were not evenly distributed by randomization of study participants; hence, unmeasured or residual confounding cannot be excluded, and ω-3 biomarker measures may in part be markers of a long-term healthy lifestyle.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The best compartment for assessing ALA has been unclear, with possible advantages to adipose tissue but relatively little prior evaluation of other compartments.

    “The best compartment for assessing ALA has also been unclear, with possible advantages to adipose tissue16 but relatively little prior evaluation of other compartments.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] Baylin A Kim MK Donovan-Palmer A Fasting whole blood as a biomarker of essential fatty acid intake in epidemiologic studies: comparison with adipose tissue and plasma Am J Epidemiol 2005 162 4 373 381 16014782 source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductcitation

    Most studies used centralized adjudication processes or registry linkage rather than self-report alone in ascertaining events, reducing information bias.

    “Most studies18–25,27–35 used centralized adjudication processes or registry linkage rather than self-report alone in ascertaining events, reducing information bias.”
    Quote in the paperSubstantial claim0 of 10 sources checked
    • cites [18] ARIC Investigators The Atherosclerosis Risk in Communities (ARIC) Study: design and objectives Am J Epidemiol 1989 129 4 687 702 2646917

      Not checked in the free run.

    • cites [19] Campos H Bailey SM Gussak LS Siles X Ordovas JM Schaefer EJ Relations of body habitus, fitness level, and cardiovascular risk factors including lipoproteins and apolipoproteins in a rural and urban Costa Rican population Arterioscler Thromb 1991 11 4 1077 1088 2065029 source

      Not checked in the free run.

    • cites [20] Fried LP Borhani NO Enright P The Cardiovascular Health Study: design and rationale Ann Epidemiol 1991 1 3 263 276 1669507 source

      Not checked in the free run.

    • cites [21] Day N Oakes S Luben R EPIC-Norfolk: study design and characteristics of the cohort: European Prospective Investigation of Cancer Br J Cancer 1999 80 1 suppl 1 95 103 10466767 source

      Not checked in the free run.

    • cites [22] Kardinaal AF van ‘t Veer P Kokl FJ EURAMIC Study: antioxidants, myocardial infarction and breast cancer: design and main hypotheses Eur J Clin Nutr 1993 47 2 suppl 2 S64 S72 8262023

      Not checked in the free run.

    • cites [23] Rimm EB Giovannucci EL Willett WC Prospective study of alcohol consumption and risk of coronary disease in men Lancet 1991 338 8765 464 468 1678444 source

      Not checked in the free run.

    • cites [24] Bartali B Benvenuti E Corsi AM Changes in anthropometric measures in men and women across the life-span: findings from the InCHIANTI study Soz Praventivmed 2002 47 5 336 348 12512227 source

      Not checked in the free run.

    • cites [25] Vanharanta M Voutilainen S Lakka TA van der Lee M Adlercreutz H Salonen JT Reduced risk of acute coronary events at high levels of mammalian lignan, enterolactone: a prospective population-based cohort study Lancet 1999 354 2112 2115 10609816 source

      Not checked in the free run.

    • cites [27] Bild DE Bluemke DA Burke GL Multi-Ethnic Study of Atherosclerosis: objectives and design Am J Epidemiol 2002 156 9 871 881 12397006 source

      Not checked in the free run.

    • cites [28] Norberg M Wall S Boman K Weinehall L The Västerbotten Intervention Programme: background, design and implications Global Health Action website 2010 http://www.globalhealthaction.net/index.php/gha/article/view/4643/5514 Accessed May 30, 2016 PMC2844807 20339479 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Study design and conductnone given

    Inclusion of all available studies substantially reduces the potential for publication bias.

    “Our inclusion of all available studies substantially reduces the potential for publication bias.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Circulating and tissue levels of EPA and DHA are strongly influenced by dietary seafood consumption, whereas DPA concentrations appear mainly derived from endogenous elongation of EPA, with very limited interconversion between DPA and DHA.

    “In addition, whereas circulating and tissue levels of EPA and DHA are strongly influenced by dietary seafood consumption, DPA concentrations appear to be mainly derived from endogenous elongation of EPA; interconversion between DPA and DHA is very limited.10”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Mozaffarian D Wu JH (n-3) fatty acids and cardiovascular health: are effects of EPA and DHA shared or complementary? J Nutr 2012 142 3 614S 625S 22279134 PMC3278271 source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductnone given

    Use of biomarkers provided measures of exposure free of recall error and allowed separate evaluation of different ω-3 PUFAs and different circulating and tissue lipid compartments.

    “Use of biomarkers provided measures of exposure free of recall error and allowed separate evaluation of different ω-3 PUFAs and different circulating and tissue lipid compartments.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    A meta-analysis of prior reports of dietary and biomarker ALA and CHD risk revealed inconsistency, perhaps due to methodologic and analytic differences.

    “However, a meta-analysis11 of prior reports of dietary and biomarker ALA and CHD risk revealed inconsistency, perhaps owing to methodologic and analytic differences in these investigations.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [11] Pan A Chen M Chowdhury R α-Linolenic acid and risk of cardiovascular disease: a systematic review and meta-analysis Am J Clin Nutr 2012 96 6 1262 1273 23076616 PMC3497923 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Adipose tissue has been suggested for measurement of fatty acids because it reflects long-term dietary intake of approximately 1 year.

    “Adipose tissue has been suggested for measurement of fatty acids because it reflects long-term dietary intake (approximately 1 year).56”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [56] Dayton S Hashimoto S Dixon W Pearce ML Composition of lipids in human serum and adipose tissue during prolonged feeding of a diet high in unsaturated fat J Lipid Res 1966 7 1 103 111 5900208 source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductreasoning

    The findings were independent of a range of major cardiovascular risk factors, and the relative specificity for fatal CHD and known biologic effects of ω-3 PUFAs argue against residual confounding as the sole explanation.

    “However, our findings were independent of a range of major cardiovascular risk factors, and the relative specificity for fatal CHD and known biologic effects of ω-3 PUFAs also argue against residual confounding as the sole explanation for our findings.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    EPA and DHA are more highly concentrated in phospholipids than other compartments, and phospholipids respond rapidly to dietary changes and may best reflect effects on membrane receptors.

    “However, EPA and DHA are more highly concentrated in phospholipids than other compartments, and phospholipids also respond rapidly to dietary changes57,58 and may best reflect effects on membrane receptors.1”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [57] Arterburn LM Hall EB Oken H Distribution, interconversion, and dose response of n-3 fatty acids in humans Am J Clin Nutr 2006 83 6 suppl 1467S 1476S 16841856

      Not checked in the free run.

    • cites [58] Conquer JA Holub BJ Effect of supplementation with different doses of DHA on the levels of circulating DHA as non-esterified fatty acid in subjects of Asian Indian background J Lipid Res 1998 39 2 286 292 9507989

      Not checked in the free run.

    • cites [1] Mozaffarian D Wu JHY Omega-3 fatty acids and cardiovascular disease: effects on risk factors, molecular pathways, and clinical events J Am Coll Cardiol 2011 58 20 2047 2067 22051327 source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    The studies included both sexes, multiple races, and a range of socioeconomic statuses across 16 countries, increasing generalizability.

    “The studies included both sexes, multiple races, and a range of socioeconomic statuses across 16 countries, increasing generalizability.”
    Quote in the paperNot a substantial claim
39 of 39

  • The paper relies on this without support.

    ω-3 PUFA biomarker concentrations reflect dietary intake of these fatty acids.

    “biomarker concentrations of seafood and plant-derived ω-3 fatty acids are associated with a lower incidence of fatal CHD.”

  • The paper relies on this without support.

    The 19 included studies are representative of free-living populations globally.

    “On the basis of available studies of free-living populations globally”

  • The paper relies on this without support.

    Earlier single-study biomarker analyses generally lacked power to examine effect differences by participant traits, medication use, or genetic variation.

    “prior individual biomarker studies were generally underpowered to explore potentially relevant differences in effects depending on underlying participant characteristics, medication use, or genetic variation.”

  • The paper relies on this without support.

    The different biomarker compartments (total plasma, phospholipids, cholesterol esters, adipose tissue) provide comparable measures of ω-3 PUFA exposure for pooling.

    “Results were first pooled separately for each biomarker compartment and then pooled together.”

  • The paper relies on this without support.

    Baseline ω-3 PUFA biomarker concentrations reflect habitual dietary intake over the relevant etiologic period.

    “Because our findings reflect habitual ω-3 exposure for primary CHD prevention”
5 of 5

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Observational studies have demonstrated an inverse association between dietary consumption of either fatty fish or omega-3 fatty acids and incident cardiovascular events.

    “Observational studies have demonstrated an inverse association between dietary consumption of either fatty fish or omega-3 fatty acids and incident cardiovascular events 1,2”

    From Effect of High-Dose Omega-3 Fatty Acids vs Corn Oil on Major Adverse Cardiovascular Events in Patients at High Cardiovascular Risk (2020) · cites this paper as [1]

    The Conclusions report that biomarkers reflecting habitual seafood and plant-based ω-3 consumption were associated with lower fatal coronary heart disease risk. The Discussion also cites observational evidence concerning fish consumption, but says associations with nonfatal myocardial infarction were less robust. The claim extends these findings to incident cardiovascular events generally and describes dietary consumption as the measured exposure, whereas this study measured biomarkers. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Dietary consumption of fatty fish or omega-3 fatty acids was associated with lower rates of incident cardiovascular events in large cohort studies.

    “The origins of this research were based on observations that dietary consumption of fatty fish or omega-3 fatty acids were associated with lower rates of incident cardiovascular events in large cohort studies. 1,2,19,20”

    From Effect of High-Dose Omega-3 Fatty Acids vs Corn Oil on Major Adverse Cardiovascular Events in Patients at High Cardiovascular Risk (2020) · cites this paper as [1]

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Different fatty acids are assigned the same nonfatal-MI result

    Major

    The abstract assigns the nonfatal-MI quintile result of RR 0.87 to ALA, whereas the Results section assigns that same result to DHA.

  • Two heterogeneity values are reported for DHA

    Minor

    For the fatal-CHD association, DHA is assigned an I2 of both 37% and 31% in consecutive statements.

2 of 2

Cites

Flagged first, then by citations

1 of the 64 references couldn’t be matched to a known paper.

Cited by

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Related

Authors
Del Gobbo, L. C., Imamura, F., Aslibekyan, S., Marklund, M., Virtanen, J. K., Wennberg, M., Yakoob, M. Y., Chiuve, S. E., dela Cruz, L., Frazier-Wood, A. C., Fretts, A. M., Guallar, E., Matsumoto, C., Prem, K., Tanaka, T., Wu, J. H. Y., Zhou, X., Helmer, C., Ingelsson, E., Yuan, J.-M., Barberger-Gateau, P., Campos, H., Chaves, P. H. M., Djoussé, L., Giles, G. G., Gómez-Aracena, J., Hodge, A. M., Hu, F. B., Jansson, J.-H., Johansson, I., Khaw, K.-T., Koh, W.-P., Lemaitre, R. N., Lind, L., Luben, R. N., Rimm, E. B., Risérus, U., Samieri, C., Franks, P. W., Siscovick, D. S., Stampfer, M., Steffen, L. M., Steffen, B. T., Tsai, M. Y., van Dam, R. M., Voutilainen, S., Willett, W. C., Woodward, M., Mozaffarian, D., & for the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Fatty Acids and Outcomes Research Consortium (FORCe)
Affiliations
  • Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California
  • University of Cambridge (GB)
  • University of Alabama at Birmingham (US)
  • Uppsala University (SE)
  • University of Eastern Finland (FI)
  • Umeå University (SE)
  • Harvard University (US)
  • Brigham and Women's Hospital (US)
  • Cancer Epidemiology Centre, Cancer Council Victoria, Victoria, Australia
  • USDA/ARS Children’s Nutrition Research Center, Baylor College of Medicine, Houston, Texas
  • University of Washington (US)
  • Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
  • National University of Singapore (SG)
  • National Institutes of Health (US)
  • The University of Sydney (AU)
  • University of Minnesota (US)
  • Université de Bordeaux (FR)
  • University of Pittsburgh (US)
  • Institut National de la Santé et de la Recherche Médicale, Institut de Santé Publique, d'Épidémiologie et de Développement, Centre IInstitut National de la Santé et de la Recherche Médicale U897-Epidemiologie-Biostatistique, Bordeaux, France
  • Florida International University (US)
  • Cancer Council Victoria (AU)
  • Universidad de Málaga (ES)
  • Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle
  • New York Academy of Medicine (US)
  • Saw Swee Hock School of Public Health, National University of Singapore, Singapore
  • Tufts University (US)
ORCID
Venue
JAMA Internal Medicine
Publisher
American Medical Association (AMA)
Published
2016-08-01
Volume
176
Issue
8
Pages
1155
ISSN
2168-6106 (ISSN-L)
DOI
10.1001/jamainternmed.2016.2925
PMC
PMC5183535
OpenAlex
W2469860611
Cited by
404
References
64
Citations by year
2026: 25 · 2025: 26 · 2024: 25 · 2023: 36 · 2022: 41 · 2021: 53 · 2020: 43 · 2019: 53 · 2018: 56 · 2017: 36 · 2016: 8
FWCI
53.39
Type
journal article
Language
en
Open access
Locations
  • JAMA Internal Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
  • Lund University Publications (Lund University) (submittedVersion)
  • Apollo (University of Cambridge) (submittedVersion, cc-by)
Funders
  • Brigham and Women's Hospital
  • University of Minnesota
  • New York Academy of Medicine
  • Florida International University
  • University of Washington
  • Duke-NUS Medical School
  • National Institute for Health and Care Research (NF-SI-0512-10114)
  • British Heart Foundation
  • University of Oxford
  • National University of Singapore
  • Agence Nationale de la Recherche (ANR-06-PNRA-0005)
  • Lunds Universitet
  • Umeå Universitet
  • National University Health System
  • George Institute for Global Health
  • National Institutes of Health (n01hc95164-17-0-1, n01hc085082-026, n01hc085081-021, n01hc085079-024, n01hc085083-027, n01hc95165-34-0-1, 5r01ca049449-18, n01hc085080-026, n01hc95161-24-0-1, n01hc095169-003, n01hc95166-21-0-1, n01hc085086-022, n01hc95162-31-0-1, n01hc95168-27-0-1, n01hc95160-18-0-1, n01hc095167-000, UL1TR001079, n01hc95163-22-0-1, n01hc55222-0-0-0, n02hl64278-6-0-0, n01hc95159-40-0-1, Z99 AG999999)
  • Medical Research Council (MC_UU_12015/5, MR/N003284/1)
  • National Institute on Alcohol Abuse and Alcoholism (R01AA011181)
  • National Institute on Aging (R01AG023629)
  • National Heart, Lung, and Blood Institute (N01 HC085086, R01HL060712, N01-HC095169, N01-HC-095165, R21HL088081, N01 HC085079, N01 HC095163, N01 HC085083, N01 HC085080, N02 HL064278, R01HL035464, N01-HC-095159, N01 HC095168, N01-HC-095162, N01-HC-095161, R01 HL026490, R01HL087641, R01HL059367, N01 HC095167, N01HC085082, U01HL080295, N01-HC-095160, R01HL081549, N01 HC055222, N01 HC095166, R01HL034595, N01 HC095164, N01 HC085081, R01HL085710, R01HL086694, R01HL034594, R01HL088521)
  • National Human Genome Research Institute (U01HG004402)
  • National Cancer Institute (R01CA040360, R01CA144034, R01CA080205, P01CA087969, R01 CA034944, R01‐CA049449, R01CA097193, P01CA055075, UM1CA182876, UM1CA186107, UM1CA167552, U01CA182876, U01CA167552)
  • National Institute of Diabetes and Digestive and Kidney Diseases (P30DK046200)
  • National Center for Research Resources (UL1RR025005)
  • National Center for Advancing Translational Sciences
  • National Institute on Minority Health and Health Disparities (R01MD009164)
Topics
  • Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Nutritional Studies and Diet
  • Life Sciences › Agricultural and Biological Sciences › Aquatic Science › Aquaculture Nutrition and Growth
Keywords
coronary artery disease, eicosapentaenoic acid, docosapentaenoic acid, docosahexaenoic acid, alpha-linolenic acid, myocardial infarction, coronary heart disease mortality, primary prevention, plasma phospholipids, cholesterol esters, adipose tissue
MeSH terms
Coronary Disease, Docosahexaenoic Acids, Fatty Acids, Unsaturated, Female, Humans, Male, Cohort Studies, Biomarkers, Fatty Acids, Omega-3, Incidence, Odds Ratio, alpha-Linolenic Acid

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-01.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-01.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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