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Background: Biomarker levels of very long-chain saturated fatty acids (VLCSFAs) have been found to be favorably associated with cardiovascular risk factors including lower risk of diabetes and reduced triglycerides. Few studies have examined the association between VLCSFAs and coronary heart disease (CHD). Aims: To assess the association of circulating arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0) with incident total, fatal, and nonfatal CHD. Methods: We used data from the Fatty Acids and Outcomes Research Consortium consisting of 15 prospective cohorts worldwide which included adults (age≥18 years) who were free of cardiovascular disease and had blood measurements of 20:0, 22:0, and 24:0 at baseline. A study protocol with standardized definitions of exposures, disease outcomes, and covariates was developed, for which each cohort conducted individual participant-level analysis. Cohort-specific associations were pooled using inverse variance-weighted meta-analysis to calculate the overall relative risk (RR) per interquintile range (difference between the 90 th and 10 th percentiles) and 95% confidence interval (CI). Results: Among 33,083 participants, 6,165 cases of total CHD were ascertained. The overall pooled RR and 95% CI were 0.96 (0.89, 1.02) for 20:0, 1.01 (0.92, 1.11) for 22:0, 0.94 (0.86, 1.02) for 24:0, and 0.96 (0.89, 1.04) for 20:0 + 22:0 + 24:0 ( Figure 1 ). However, we noted heterogeneity by lipid compartments, with significant inverse associations for higher 22:0 [0.77 (0.62, 0.96)], 24:0 [0.61 (0.49, 0.77)], and 20:0 + 22:0 + 24:0 [0.73 (0.60, 0.89)] in the total plasma/serum compartment but not in the phospholipid compartment. Similar associations were observed for fatal and nonfatal CHD and when using a random-effects model. Conclusion: Higher circulating VLCSFAs were not associated with total CHD in a global consortium of prospective studies. The finding of an inverse association with total CHD for VLCSFAs in the total plasma/serum compartment warrants further research.

Background: Several recent studies have linked higher blood levels of the long-chain omega-3 polyunsaturated fatty acids (PUFAs) with lower risk of certain disease outcomes, in particular cardiovascular disease (CVD). Limited studies have evaluated associations between n-3 PUFA levels and total and cause-specific mortality. Methods: We meta-analyzed the association of circulating omega-3 PUFAs with total and cause-specific mortality from 15 distinct cohorts in 10 countries following a total of 36,840 individuals (baseline average age 66 yrs; 47% female; median follow-up 13.7 yrs), with 11,635 deaths. Total mortality, and 3 cause-specific mortalities (CVD, cancer or other), were separately predicted by levels of the long chain omega-3 PUFAs eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), docosahexaenoic acid (DHA) and the Omega-3 index (EPA+DHA), as well as levels of alpha-linolenic acid (ALA, an intermediate chain n-3 PUFA). Using cohort-specific fatty acid levels (range from 10 th to 90 th percentiles), each cohort fit a Cox regression model adjusting for demographics, health related covariates, and n-6 PUFA levels. Cohort-specific estimates were pooled with inverse-variance weighted meta-analysis. Results: Higher levels of EPA, DPA, DHA and the Omega-3 index were all associated with lower all-cause mortality [EPA meta-analysis Hazard Ratio (HR)=0.90 (95% CI: 0.85, 0.95), DPA HR=0.84 (95% CI: 0.77, 0.91), DHA HR=0.84 (95% CI: 0.75, 0.93), Omega-3 index HR = 0.84 (95% CI 0.77, 0.92) (Figure)], as well as for each cause-specific mortality (CVD, cancer and other; HRs from 0.85 to 0.92). ALA showed no association with total-mortality or cause-specific mortality [HRs from 0.97 to 1.00)]. Conclusions: We have found strong evidence of inverse associations between long-chain omega-3 PUFA levels and all-cause and cause-specific mortality. Further controlled studies are needed in order to determine the extent to which these observations represent a causal or coincidental relationships.

International audience; Background: Prevalences of Alcohol Use Disorders (AUDs) and Mental Health Disorders (MHDs) in many individual countries have been reported but there are few cross-national studies. The WHO World Mental Health (WMH) Survey Initiative standardizes methodological factors facilitating comparison of the prevalences and associated factors of AUDs in a large number of countries to identify differences and commonalities.Methods: Lifetime and 12-month prevalence estimates of DSM-IV AUDs, MHDs, and associations were assessed in the 29 WMH surveys using the WHO CIDI 3.0.Results: Prevalence estimates of alcohol use and AUD across countries and WHO regions varied widely. Mean lifetime prevalence of alcohol use in all countries combined was 80%, ranging from 3.8% to 97.1%. Combined average population lifetime and 12-month prevalence of AUDs were 8.6% and 2.2% respectively and 10.7% and 4.4% among non-abstainers. Of individuals with a lifetime AUD, 43.9% had at least one lifetime MHD and 17.9% of respondents with a lifetime MHD had a lifetime AUD. For most comorbidity combinations, the MHD preceded the onset of the AUD. AUD prevalence was much higher for men than women. 15% of all lifetime AUD cases developed before age 18. Higher household income and being older at time of interview, married, and more educated, were associated with a lower risk for lifetime AUD and AUD persistence.Conclusions: Prevalence of alcohol use and AUD is high overall, with large variation worldwide. The WMH surveys corroborate the wide geographic consistency of a number of well-documented clinical and epidemiological findings and patterns.

The aim of this study was to evaluate the reliability and validity of the State-Trait Hopelessness Scale (STHS) in patients with heart disease who report moderate to severe state hopelessness.Reliability, concurrent validity, and convergent validity were evaluated for 20 patients.Cronbach's α for the State and Trait subscales were .81 and .79, respectively. Strong correlations between the State Hopelessness Subscale and Patient Health Questionnaire-9 (r = 0.77, P.001), State Hope Scale (r = -0.75, P.001), EQ-5D-5L (r = 0.59, P.005), and PROMIS-29 domains of depression (P = .72, P.001), fatigue (P = .61, P.001), and social roles (P = .45, P = .047) were found. There were strong correlations between the Trait Hopelessness Subscale and Trait Hope Scale (r = -0.58, P.005), State Hope Scale (r = -0.49, P = .03), and PROMIS-29 fatigue domain (r = 0.54, P = .015).Findings support the reliability and validity of the STHS for evaluation of hopelessness in patients with heart disease.

The neutrophil-lymphocyte ratio (NLR) is a biomarker of systemic inflammation and measures innate-adaptive immune system balance. The omega-3-index (O3I) measures the amount of EPA+DHA in blood. Both a low O3I and an elevated NLR are associated with increased risk for chronic disease and mortality, including cardiovascular diseases and cancer. Hypothesizing that low O3I may partly contribute to systemic chronic inflammation, we asked if a relationship existed between O3I and NLR in healthy adults (≥18 y, n = 28,871, 51% female) without inflammation [C-reactive protein (CRP)3 mg/mL)] who underwent a routine clinical assessment. NLR was inversely associated with O3I before (p 0.0001) and after adjusting for age, sex, BMI, and CRP (p 0.0001). Pearson correlations of other variables with NLR were r = 0.06 (CRP), r = 0.14 (age), and r = 0.01(BMI). In this healthy population, an O3I 6.6% was associated with increasing NLR whereas NLR remained relatively constant (low) when O3I 6.6%, suggestive of a quiescent, balanced immune system.

Objective: Hopelessness is present in 27% of patients with ischaemic heart disease (IHD), can persist for 12 months and is associated with lack of physical activity (PA). No interventions have been tested to increase PA in IHD patients who report hopelessness. This study evaluated the feasibility of conducting a randomised controlled trial to investigate the effectiveness of the Heart Up! intervention, designed to reduce hopelessness through enhanced PA in IHD patients. It was hypothesised that increased PA would be identified in the intervention group. Setting: Patients were recruited from a large teaching hospital in the Midwestern USA. Data collection occurred in the patient’s home at 1 and 8 weeks after hospital discharge. Methods: A three-group design was used. Eligible patients were randomised to (1) motivational social support (MSS) from a nurse, (2) MSS from a nurse with social support from a significant other support (SOS) or (3) control. MSS-only and MSS-SOS recipients received motivational interviewing followed by 6 weeks of social support text messages from a nurse. MSS-SOS participants additionally received social support text messages from a significant other. Control participants received the usual care. Feasibility outcomes included recruitment and retention rates, patient acceptability and patient satisfaction. An accelerometer measured PA. Results: Of the 156 patients screened for the study, 43 met the inclusion criteria. Of eligible patients, 69.8% ( n = 30) enrolled and 67% ( n = 20) completed the study. Patients in the MSS and MSS-SOS groups expressed satisfaction with the intervention components (86% with motivational interviewing, 77% with nurse texts and 100% with significant other texts). Although differences were not statistically significant, a medium effect size for change in PA was identified in the MSS-SOS group compared to the other two groups. Conclusion: Study findings demonstrate the feasibility of the Heart Up! intervention and support testing its efficacy in a randomised controlled trial.

The popularization of biobanks provides an unprecedented amount of genetic and phenotypic information that can be used to research the relationship between genetics and human health. Despite the opportunities these datasets provide, they also pose many problems associated with computational time and costs, data size and transfer, and privacy and security. The publishing of summary statistics from these biobanks, and the use of them in a variety of downstream statistical analyses, alleviates many of these logistical problems. However, major questions remain about how to use summary statistics in all but the simplest downstream applications. Here, we present a novel approach to utilize basic summary statistics (estimates from single marker regressions on single phenotypes) to evaluate more complex phenotypes using multivariate methods. In particular, we present a covariate-adjusted method for conducting principal component analysis (PCA) utilizing only biobank summary statistics. We validate exact formulas for this method, as well as provide a framework of estimation when specific summary statistics are not available, through simulation. We apply our method to a real data set of fatty acid and genomic data.

Author(s): Arkin, Adam P; Cottingham, Robert W; Henry, Christopher S; Harris, Nomi L; Stevens, Rick L; Maslov, Sergei; Dehal, Paramvir; Ware, Doreen; Perez, Fernando; Canon, Shane; Sneddon, Michael W; Henderson, Matthew L; Riehl, William J; Murphy-Olson, Dan; Chan, Stephen Y; Kamimura, Roy T; Kumari, Sunita; Drake, Meghan M; Brettin, Thomas S; Glass, Elizabeth M; Chivian, Dylan; Gunter, Dan; Weston, David J; Allen, Benjamin H; Baumohl, Jason; Best, Aaron A; Bowen, Ben; Brenner, Steven E; Bun, Christopher C; Chandonia, John-Marc; Chia, Jer-Ming; Colasanti, Ric; Conrad, Neal; Davis, James J; Davison, Brian H; DeJongh, Matthew; Devoid, Scott; Dietrich, Emily; Dubchak, Inna; Edirisinghe, Janaka N; Fang, Gang; Faria, Jose P; Frybarger, Paul M; Gerlach, Wolfgang; Gerstein, Mark; Greiner, Annette; Gurtowski, James; Haun, Holly L; He, Fei; Jain, Rashmi; Joachimiak, Marcin P; Keegan, Kevin P; Kondo, Shinnosuke; Kumar, Vivek; Land, Miriam L; Meyer, Folker; Mills, Marissa; Novichkov, Pavel S; Oh, Taeyun; Olsen, Gary J; Olson, Robert; Parrello, Bruce; Pasternak, Shiran; Pearson, Erik; Poon, Sarah S; Price, Gavin A; Ramakrishnan, Srividya; Ranjan, Priya; Ronald, Pamela C; Schatz, Michael C; Seaver, Samuel MD; Shukla, Maulik; Sutormin, Roman A; Syed, Mustafa H; Thomason, James; Tintle, Nathan L; Wang, Daifeng; Xia, Fangfang; Yoo, Hyunseung; Yoo, Shinjae; Yu, Dantong

The recent simulation-based inference (SBI) movement in algebra-based introductory statistics courses (Stat 101) has provided preliminary evidence of improved student conceptual understanding and retention. However, little is known about whether these positive effects are preferentially distributed across types of students entering the course. We consider how two metrics of Stat 101 student preparation (precourse performance on concept inventory and math ACT score) may or may not be associated with end of course student performance on conceptual inventories. Students across all preparation levels tended to show improvement in Stat 101, but more improvement was observed across all student preparation levels in early versions of a SBI course. Furthermore, students' gains tended to be similar regardless of whether students entered the course with more preparation or less. Recent data on a sample of students using a current version of an SBI course showed similar results, though direct comparison with non-SBI students was not possible. Overall, our analysis provides additional evidence that SBI curricula are effective at improving students' conceptual understanding of statistical ideas postcourse regardless student preparation. Further work is needed to better understand nuances of student improvement based on other student demographics, prior coursework as well as instructor and institutional variables.

OBJECTIVES: Higher omega-3 fatty acid blood levels, as assessed by the Omega-3 Index (O3I, erythrocyte EPA + DHA expressed as a % of total fatty acids), have been linked with lower risk for cardiovascular disease and total mortality. Seafood is an excellent source of EPA and DHA. The purpose of this study was to determine if individuals living in a coastal US city (Newport, RI) with direct access to fresh seafood have higher O3I levels than people living in inland cities. METHODS: Dried blood spot samples were collected from a convenience sample of people attending a sponsored health fair on the boardwalk in Newport, RI between July and August 2019. Attendees interested in obtaining their O3I signed a consent form before testing and then provided a drop of blood for testing. As a comparator inland group, we used published data (Harris et al. PLEFA 2019;148:30–34) from 7 US cities in the “stroke belt” (note, only one of the 7 cities was coastal, Jacksonville, FL). Dried blood samples were analyzed for the O3I by gas chromatography in both settings. RESULTS: The Newport sample included 234 individuals, 50/50 male/female, with a mean (SD) age of 46 (16) years. The 7 cities comparator cohort contained 2177 subjects, with a mean age of 48 (16) years and of those reporting gender, 78% were female. The mean (SD) O3I in Newport was 5.15% (1.37%), whereas in the 7 cities study it was 4.42% (1.12%; P 8% (considered optimal) was found in 3% of the Newport sample compared to 1.2% in the 7 cities study (P = 0.19). CONCLUSIONS: These data support our hypothesis that the O3I is higher in populations living in a coastal city than those living inland. Still, only 3% of individuals with immediate access to fresh seafood had O3I levels in the optimal zone. Given the documented health benefits of having an optimal O3I, increased intakes of EPA and DHA from fish and other dietary sources or supplementation should be recommended. FUNDING SOURCES: RB Health (US) LLC.

BACKGROUND: The roles of omega-3 (n3) fatty acids [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] and low-dose aspirin in the primary prevention of ischemic cardiovascular disease (CVD) are controversial. Since omega-3 (n3) fatty acids and aspirin affect cyclooxygenase activity in platelets, there could be a clinically-relevant effect of aspirin combined with a particular n3 fatty acid level present in each individual. METHODS: RBC EPA+DHA, arachidonic acid (AA) and docosapentaenoic acid (DPA) were measured in 2500 participants without known CVD in the Framingham Heart Study. We then tested for interactions with reported aspirin use (1004 reported use and 1494 did not) on CVD outcomes. The median follow-up was 7.2 years. RESULTS: Having RBC EPA+DHA in the second quintile (4.2–4.9% of total fatty acids) was associated with significantly reduced risk for future CVD events (relative to the first quintile

Background and aims A recent 19-cohort meta-analysis examined the relationships between biomarkers of omega-3 fatty acids and risk for coronary heart disease (CHD). That study did not, however, report hazard ratios (HRs) specifically as a function of erythrocyte eicosapentaenoic (EPA) plus docosahexaenoic (DHA) levels, a metric called the Omega-3 Index in which EPA + DHA content is expressed as a percent of total fatty acids. The Omega-3 Index has been used in several recent studies and is a validated biomarker of omega-3 fatty acid tissue levels, but additional data are needed to confirm (or refute) the originally-proposed clinical cut-points of Methods The present study was therefore undertaken using published data from this meta-analysis to estimate HRs per 1-SD increase in the Omega-3 Index and median quintile values for this metric across 10 of the cohorts for which the needed data were available. Results The overall mean (SD) for the Omega-3 Index in these 10 cohort studies was 6.1% (2.1%), and the HR for a 1-SD increase was 0.85 (95% confidence interval, 0.80–0.91). Median quintile 1 and 5 levels were 4.2% vs. 8.3%, respectively. Based on these values, we estimate that risk for fatal CHD would have been reduced by about 30% moving from an Omega-3 Index of 4%–8%. Conclusions These findings support the use of 8% as reasonable therapeutic targets for the Omega-3 Index.

BackgroundNon-­resolving activation of immune responses is central to the pathogenesis of heart failure (HF). Free fatty acid receptor 4 (Ffar4) is a G-protein coupled receptor (GPR) for medium-and long-chain fatty acids (FA) that regulates metabolism and attenuates inflammation in diabetes and obesity. Here, we tested the hypothesis that Ffar4 functions as a cardioprotective nutrient sensor that resolves inflammation to maintain cardiac homeostasis.MethodsMice with systemic deletion of Ffar4 (Ffar4KO) were subjected to pressure overload by transverse aortic constriction (TAC). Transcriptome analysis of cardiac myocytes was performed three days post-TAC. Additionally, Ffar4-mediated effects on inflammatory oxylipin production in cardiac myocytes and oxylipin composition in plasma lipoproteins were evaluated.ResultsIn Ffar4KO mice, TAC induced more severe remodeling, identifying an entirely novel cardioprotective role for Ffar4 in the heart. Transcriptome analysis 3-days post-TAC indicated a failure to induce cell death and inflammatory genes in Ffar4KO cardiac myocytes, as well as a specific failure to induce cytoplasmic phospholipase A2α (cPLA2α) signaling genes. In cardiac myocytes, Ffar4 signaling through cPLA2α-cytochrome p450 ω/ω-1 hydroxylase induced production of the EPA-derived anti-inflammatory oxylipin 18-hydroxyeicosapentaenoic acid (18-HEPE). Systemically, loss of Ffar4 altered oxylipin content in circulating plasma lipoproteins consistent with a loss of anti-inflammatory oxylipins at baseline, and inability to produce both pro-inflammatory and pro-resolving oxylipins following TAC. Finally, we confirmed that Ffar4 is expressed in human heart and down-regulated in HF.ConclusionsOur results identify a novel function for Ffar4 in the heart as a FA nutrient sensor that resolves inflammation to maintain cardiac homeostasis.

Background The impact of adverse childhood experiences (ACEs) on adult life outcomes is well-documented by a considerable body of research. This study investigates the relationship between ACEs and both physical and mental health outcomes in a nationally representative sample of Ukrainian adults. Objective The aim of this study was to analyze whether ACEs are associated with lifetime physical and mental health outcomes in a nationally representative sample of Ukrainian adults. Participants and Setting In 2002, the World Mental Health Composite International Diagnostic Interview (WMH-CIDI) was administered to a national probability sample of Ukrainian adults (n = 4725). Methods Associations between ACEs and later life physical and mental health outcomes are examined using logistic regression models. Results ACEs were significantly correlated with poor later life mental and physical health. Participants with three or more ACEs were most likely to have chronic pain, cardiovascular disease, other disease, depressive disorders, anxiety disorders, substance abuse disorders, and all disability metrics analyzed. Adjusted odds ratios for these models ranged from 1.80 to 3.81. Additionally, we found a large association between the number of ACES and later negative health outcomes. Conclusions Our results indicate that in Ukraine, ACEs have a strong negative effect on later life mental and physical health. Further research is needed to explore specific ACEs and examine potential mediators such as social support in the relationship between ACEs and health outcomes.

OBJECTIVES: To assess prospective association between circulating biomarkers of individual trans fatty acids (TFAs) and incident type 2 diabetes (T2D) in diverse populations. METHODS: A harmonized analysis of individual level data was conducted for TFA biomarkers and incident T2D by pooling ten prospective cohort or nested-case-control studies from five countries (Australia, Germany, Iceland, UK, and USA). Fatty acids (FAs) were measured in plasma phospholipid, red blood cell membrane phospholipid, or total plasma collected between 1990–2008 from 22,711 participants aged ≥18 years without prevalent diabetes. Evaluated TFAs included trans-16:1n-9, sum of trans-18:1 isomers (trans-18:1n6 to trans-18:1n12), sum of trans-18:2 isomers (cis/trans-18:2, trans/cis-18:2, trans/trans-18:2), and individual trans-18:2 isomers. The multivariable-adjusted relative risk or odds ratio was estimated in each cohort by lipid compartments using a pre-specified protocol for definitions of exposures, covariates, and outcomes for statistical analysis. Association estimates were pooled using fixed-effects inverse-variance weighted meta-analysis. RESULTS: During an average maximum of 14 years of follow-up, 2244 cases of incident T2D were identified. Median levels of TFAs across cohorts were 0.05–0.18% total FAs for trans-16:1n-9, 0.09–2.05% for total trans-18:1, 0.10–0.73% for total trans-18:2, and 0.01–0.36% for individual trans-18:2 isomers. In overall pooled analysis, TFAs evaluated per inter-quintile range were not significantly associated with risk of T2D (Figure 1). Findings were consistent when TFAs were assessed categorically in study specific-quintiles, and when associations were pooled within lipid compartment (i.e., phospholipids vs. total plasma). CONCLUSIONS: Overall, biomarker levels of TFAs were not significantly associated with risk of incident T2D in this international pooling project. Findings may be due to mixed TFA sources (industrial vs. ruminant), a general decline in TFA exposure during this period, or no effect of circulating TFA on diabetes. Associations of TFA biomarkers with T2D at higher exposures should be investigated. FUNDING SOURCES: See Table 1. SUPPORTING TABLES, IMAGES AND/OR GRAPHS

Background: Global dietary recommendations for and cardiovascular effects of linoleic acid, the major dietary omega-6 fatty acid, and its major metabolite, arachidonic acid, remain controversial. To address this uncertainty and inform international recommendations, we evaluated how in vivo circulating and tissue levels of linoleic acid (LA) and arachidonic acid (AA) relate to incident cardiovascular disease (CVD) across multiple international studies. Methods: We performed harmonized, de novo, individual-level analyses in a global consortium of 30 prospective observational studies from 13 countries. Multivariable-adjusted associations of circulating and adipose tissue LA and AA biomarkers with incident total CVD and subtypes (coronary heart disease, ischemic stroke, cardiovascular mortality) were investigated according to a prespecified analytic plan. Levels of LA and AA, measured as the percentage of total fatty acids, were evaluated linearly according to their interquintile range (ie, the range between the midpoint of the first and fifth quintiles), and categorically by quintiles. Study-specific results were pooled using inverse-variance–weighted meta-analysis. Heterogeneity was explored by age, sex, race, diabetes mellitus, statin use, aspirin use, omega-3 levels, and fatty acid desaturase 1 genotype (when available). Results: In 30 prospective studies with medians of follow-up ranging 2.5 to 31.9 years, 15 198 incident cardiovascular events occurred among 68 659 participants. Higher levels of LA were significantly associated with lower risks of total CVD, cardiovascular mortality, and ischemic stroke, with hazard ratios per interquintile range of 0.93 (95% CI, 0.88–0.99), 0.78 (0.70–0.85), and 0.88 (0.79–0.98), respectively, and nonsignificantly with lower coronary heart disease risk (0.94; 0.88–1.00). Relationships were similar for LA evaluated across quintiles. AA levels were not associated with higher risk of cardiovascular outcomes; in a comparison of extreme quintiles, higher levels were associated with lower risk of total CVD (0.92; 0.86–0.99). No consistent heterogeneity by population subgroups was identified in the observed relationships. Conclusions: In pooled global analyses, higher in vivo circulating and tissue levels of LA and possibly AA were associated with lower risk of major cardiovascular events. These results support a favorable role for LA in CVD prevention.

International audience; BACKGROUND:Saturated fatty acids (SFAs) of different chain lengths have unique metabolic and biological effects, and a small number of recent studies suggest that higher circulating concentrations of the very-long-chain SFAs (VLSFAs) arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0) are associated with a lower risk of diabetes. Confirmation of these findings in a large and diverse population is needed.OBJECTIVE:We investigated the associations of circulating VLSFAs 20:0, 22:0, and 24:0 with incident type 2 diabetes in prospective studies.METHODS:Twelve studies that are part of the Fatty Acids and Outcomes Research Consortium participated in the analysis. Using Cox or logistic regression within studies and an inverse-variance-weighted meta-analysis across studies, we examined the associations of VLSFAs 20:0, 22:0, and 24:0 with incident diabetes among 51,431 participants.RESULTS:There were 14,276 cases of incident diabetes across participating studies. Higher circulating concentrations of 20:0, 22:0, and 24:0 were each associated with a lower risk of incident diabetes. Pooling across cohorts, the RR (95% CI) for incident diabetes comparing the 90th percentile to the 10th percentile was 0.78 (0.70, 0.87) for 20:0, 0.84 (0.77, 0.91) for 22:0, and 0.75 (0.69, 0.83) for 24:0 after adjustment for demographic, lifestyle, adiposity, and other health factors. Results were fully attenuated in exploratory models that adjusted for circulating 16:0 and triglycerides.CONCLUSIONS:Results from this pooled analysis indicate that higher concentrations of circulating VLSFAs 20:0, 22:0, and 24:0 are each associated with a lower risk of diabetes.

Background: Effects of omega-3 fatty acids on the prevention of type 2 diabetes (T2D) are unclear. Relatively few prospective studies have utilized objective omega-3 biomarkers to assess risk. Aims: To assess the prospective relationship between circulating and tissue levels of alpha linoleic acid (ALA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA), with respect to risk of T2D. Methods: A global consortium of 20 prospective cohort studies from 14 nations with assessments of ALA, EPA, DPA, or DHA in adults (age > 18 years) were identified through July 2017 and included in this investigation. A pre-specified analytic protocol, including definitions for exposures, covariate list, disease outcome definitions, and subgroup analyses was developed and followed in new participant-level cohort analysis. Associations were pooled using inverse variance-weighted meta-analysis. Results: Among 65,147 participants, 16,693 incident cases of T2D occurred during follow-up (median follow-up in the cohorts ranged from 2.5 to 21.2 years). In pooled multivariate analysis, per interquintile range (difference between the midpoints of the first and fifth quintile for each fatty acid), EPA, DPA, DHA, and their sum ( Figure 1 ) were associated with 8%, 21%, 18%, and 19% lower risk of T2D, respectively (all P Conclusion: Higher circulating and tissue biomarkers of seafood-derived omega-3 fatty acids, EPA, DPA, and DHA, were associated with lower risk of T2D in a global consortium of prospective studies. Plant-derived ALA was not significantly associated with risk.

The Omega-3 Index (O3I; erythrocyte EPA+DHA as a percent of total fatty acids) is inversely related to risk for cardiovascular disease (CVD). The cardioprotective target O3I is 8%-12%. O3I levels in American regions with high CVD risk are poorly characterized.To determine the O3I in individuals participating in a Seafood Nutrition Partnership (SNP) survey in seven US cities in the CVD "belt."Fingerstick blood samples were analyzed for the O3I.The SNP cohort (n = 2177) had a mean (SD) O3I of 4.42% (1.12%). Only 1.2% were in the desirable range, whereas 42% had an undesirable (4%) O3I. The mean (SD) O3I in a subset of 772 SNP subjects who were matched for age and sex with the Framingham study was 4.6% (1.2%) compared 5.3% (1.6%) in the Framingham cohort (p 0.0001).Individuals in the CVD "belt" had relatively low O3I levels. Since in other settings, a low O3I is associated with increased risk for CVD, this may be one factor contributing to the higher risk for CVD in this region of the US.

BACKGROUND Supplemental long-chain omega-3 (n-3) fatty acids (EPA and DHA) raise erythrocyte EPA + DHA [omega-3 index (O3I)] concentrations, but the magnitude or variability of this effect is unclear. OBJECTIVE The purpose of this study was to model the effects of supplemental EPA + DHA on the O3I. METHODS Deidentified data from 1422 individuals from 14 published n-3 intervention trials were included. Variables considered included dose, baseline O3I, sex, age, weight, height, chemical form [ethyl ester (EE) compared with triglyceride (TG)], and duration of treatment. The O3I was measured by the same method in all included studies. Variables were selected by stepwise regression using the Bayesian information criterion. RESULTS Individuals supplemented with EPA + DHA (n = 846) took a mean ± SD of 1983 ± 1297 mg/d, and the placebo controls (n = 576) took none. The mean duration of supplementation was 13.6 ± 6.0 wk. The O3I increased from 4.9% ± 1.7% to 8.1% ± 2.7% in the supplemented individuals ( P

Previous studies have suggested that omega-3 polyunsaturated fatty acids (n-3 PUFA) can favorably influence cardiac autonomic tone. However, data regarding n-3 PUFA status and heart rate recovery (HRR) in healthy adults are sparse.To examine the association between n-3 PUFA status and HRR.Participants included 13,912 patients who underwent a comprehensive examination at the Cooper Clinic, Dallas TX. Fitness was determined from a maximal exercise test. HRR was calculated by subtracting the heart rate at 1, 3, and 5 min of an active recovery period from the maximal heart rate. Participants were categorized as having a low (4%), normal (4-8%) or optimal (8%) Omega-3 Index (O3I) (i.e., erythrocyte levels of eicosapentaenoic and docosahexaenoic acids). Multiple linear regression was used to model the association between O3I and HRR adjusting for age, maximal METs, body mass index, and smoking by sex.Higher categories of O3I were associated with greater HRR at 1 min (men: 23.7, 23.9, 24.6 beats/min; women: 23.9, 24.6, 25.9 and 3 min (men: 52.4, 52.9, 53.6 beats/min; women: 51.9, 53.4, 54.6), p trend0.01 for all. Corresponding HRR at 5 min were (men: 60.0, 60.2, 60.7 beats/min, p trend=0.09; women: 59.4, 60.8, 61.6, p trend0.001). The HRR gradients across O3I categories were steeper in women than men at 1, 3, and 5 min (p0.03 for all sex x O3I category interactions with HRR).A direct relationship between HRR and O3I values was observed in both men and women, with a steeper gradient in women. These findings suggest a potential cardioprotective mechanism for n-3 PUFA.

Exercise reduces morbidity and mortality for patients with heart disease. Despite clear guidelines and known benefits, most cardiac patients do not meet current exercise recommendations. Physician endorsement positively affects patient participation in hospital-based Phase II cardiac rehabilitation programs, yet the importance of physician recommendation for home-based cardiac rehabilitation exercise is unknown. A prospective observational design was used to examine predictors of both home-based and Phase II rehabilitation exercise in a sample of 251 patients with coronary heart disease. Regression analyses were done to examine demographic and clinical characteristics, physical functioning, and patient’s report of physician recommendation for exercise. Patients with a strong physician referral, who were married and older, were more likely to participate in Phase II exercise. Increased strength of physician recommendation was the unique predictor of home-based exercise. Further research is needed to examine how health professionals can motivate cardiac patients to exercise in home and outpatient settings.

“Simulation-based inference” (e.g., bootstrapping and randomization tests) has been advocated recently with the goal of improving student understanding of statistical inference, as well as the statistical investigative process as a whole. Preliminary assessment data have been largely positive. This article describes the analysis of the first year of data from a multi-institution assessment effort by instructors using such an approach in a college-level introductory statistics course, some for the first time. We examine several pre-/post-measures of student attitudes and conceptual understanding of several topics in the introductory course. We highlight some patterns in the data, focusing on student level and instructor level variables and the application of hierarchical modeling to these data. One observation of interest is that the newer instructors see very similar gains to more experienced instructors, but we also look to how the data collection and analysis can be improved for future years, es...

The authors regret that the abovementioned article published online September 16, 2019, had an error in the author affiliations. The edited author affiliations are shown above. The authors also regret that the names of the WHO World Mental Health Survey Collaborators were omitted from the end of the article. “The WHO World Mental Health Survey collaborators are Sergio Aguilar-Gaxiola, MD, PhD; Ali Al-Hamzawi, MD; Mohammed Salih Al-Kaisy, MD; Jordi Alonso, MD, PhD; Laura Helena Andrade, MD, PhD; Lukoye Atwoli, MD, PhD; Corina Benjet, PhD; Guilherme Borges, ScD; Evelyn J. Bromet, PhD; Ronny Bruffaerts, PhD; Brendan Bunting, PhD; Jose Miguel Caldas-de-Almeida, MD, PhD; Graca Cardoso, MD, PhD; Somnath Chatterji, MD; Alfredo H. Cia, MD; Louisa Degenhardt, PhD; Koen Demyttenaere, MD, PhD; Silvia Florescu, MD, PhD; Giovanni de Girolamo, MD; Oye Gureje, MD, DSc, FRCPsych; Josep Maria Haro, MD, PhD; Meredith Harris, PhD; Hristo Hinkov, MD, PhD; Chi-yi Hu, MD, PhD; Peter de Jonge, PhD; Aimee Nasser Karam, PhD; Elie G. Karam, MD; Norito Kawakami, MD, DMSc; Ronald C. Kessler, PhD; Andrzej Kiejna, MD, PhD; Viviane Kovess-Masfety, MD, PhD; Sing Lee, MB, BS; Jean-Pierre Lepine, MD; John McGrath, MD, PhD; Maria Elena Medina-Mora, PhD; Zeina Mneimneh, PhD; Jacek Moskalewicz, PhD; Fernando Navarro-Mateu, MD, PhD; Marina Piazza, MPH, ScD; Jose Posada-Villa, MD; Kate M. Scott, PhD; Tim Slade, PhD; Juan Carlos Stagnaro, MD, PhD; Dan J. Stein, FRCPC, PhD; Margreet ten Have, PhD; Yolanda Torres, MPH, Dra.HC; Maria Carmen Viana, MD, PhD; Daniel V. Vigo, MD, DrPH; Harvey Whiteford, MBBS, PhD; David R. Williams, MPH, PhD; and Bogdan Wojtyniak, ScD.” The authors would like to apologise for any inconvenience caused.

As genetic sequencing becomes less expensive and data sets linking genetic data and medical records (e.g., Biobanks) become larger and more common, issues of data privacy and computational challenges become more necessary to address in order to realize the benefits of these datasets. One possibility for alleviating these issues is through the use of already-computed summary statistics (e.g., slopes and standard errors from a regression model of a phenotype on a genotype). If groups share summary statistics from their analyses of biobanks, many of the privacy issues and computational challenges concerning the access of these data could be bypassed. In this paper we explore the possibility of using summary statistics from simple linear models of phenotype on genotype in order to make inferences about more complex phenotypes (those that are derived from two or more simple phenotypes). We provide exact formulas for the slope, intercept, and standard error of the slope for linear regressions when combining phenotypes. Derived equations are validated via simulation and tested on a real data set exploring the genetics of fatty acids.

In the search for an understanding of how genetic variation contributes to the heritability of common human disease, the potential role of epigenetic factors, such as methylation, is being explored with increasing frequency. Although standard analyses test for associations between methylation levels at individual cytosine-phosphate-guanine (CpG) sites and phenotypes of interest, some investigators have begun testing for methylation and how methylation may modulate the effects of genetic polymorphisms on phenotypes. In our analysis, we used both a genome-wide and candidate gene approach to investigate potential single-nucleotide polymorphism (SNP)–CpG interactions on changes in triglyceride levels. Although we were able to identify numerous loci of interest when using an exploratory significance threshold, we did not identify any significant interactions using a strict genome-wide significance threshold. We were also able to identify numerous loci using the candidate gene approach, in which we focused on 18 genes with prior evidence of association of triglyceride levels. In particular, we identified GALNT2 loci as containing potential CpG sites that moderate the impact of genetic polymorphisms on triglyceride levels. Further work is needed to provide clear guidance on analytic strategies for testing SNP–CpG interactions, although leveraging prior biological understanding may be needed to improve statistical power in data sets with smaller sample sizes.

GAW20 provided a platform for developing and evaluating statistical methods to analyze human lipid-related phenotypes, DNA methylation, and single-nucleotide markers in a study involving a pharmaceutical intervention. In this article, we present an overview of the data sets and the contributions analyzing these data. The data, donated by the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) investigators, included data from 188 families (N = 1105) which included genome-wide DNA methylation data before and after a 3-week treatment with fenofibrate, single-nucleotide polymorphisms, metabolic syndrome components before and after treatment, and a variety of covariates. The contributions from individual research groups were extensively discussed prior, during, and after the Workshop in groups based on discussion themes, before being submitted for publication.

Background: The extent to which omega-3 fatty acid (FA) status is related to risk for death from any cause and for incident cardiovascular disease (CVD) remains controversial. Objective: To examine this association in the Framingham Heart Study (FHS). Design: Prospective and observational. Setting: FHS Offspring cohort. Measurements: The primary exposure marker was red blood cell (RBC) levels of eicosapentaenoic and docosahexaenoic acids (EPA and DHA; the Omega-3 Index) which was measured at baseline. Secondary markers included RBC EPA, DHA, alpha-linolenic and docosapentaenoic (n-3) acids. Outcomes included mortality (total, CVD, cancer, and other) and total CVD events. Median follow-up was 7.3 years. Cox proportional hazards models were adjusted for 18 demographic characteristics, clinical status, therapies and other CVD risk factors including C-reactive protein levels. Results: Among the 2500 participants (mean age 66 years, 54% women; all free of CVD at baseline) there were 350 deaths (58 from CVD, 146 from cancer, 128 from other known causes, and 18 from unknown causes). There were 245 CVD events. In multivariable-adjusted analyses, a higher Omega-3 Index was associated with significantly lower risks (p-values for trends across quintiles) for total mortality (p=0.02) and non-CVD, non-cancer mortality (p = 0.009; Figure), and for total CVD events (p=0.008). Those in the highest versus the lowest Omega-3 Index quintiles (i.e., >6.8% vs. Limitations: Relatively short follow-up time and a single exposure assessment. Conclusions: A higher Omega-3 Index was associated with reduced risk of both CVD and all-cause mortality.

Rhizomes facilitate the wintering and vegetative propagation of many perennial grasses. Sorghum halepense (johnsongrass) is an aggressive perennial grass that relies on a robust rhizome system to persist through winters and reproduce asexually from its rootstock nodes. This study aimed to sequence and assemble expressed transcripts within the johnsongrass rhizome. A de novo transcriptome assembly was generated from a single johnsongrass rhizome meristem tissue sample. A total of 141,176 probable protein-coding sequences from the assembly were identified and assigned gene ontology terms using Blast2GO. The johnsongrass assembly was compared to Sorghum bicolor, a related non-rhizomatous species, along with an assembly of similar rhizome tissue from the perennial grain crop Thinopyrum intermedium. The presence/absence analysis yielded a set of 259 johnsongrass contigs that are likely associated with rhizome development.

Background We aimed to investigate prospective associations of circulating or adipose tissue odd-chain fatty acids 15:0 and 17:0 and trans-palmitoleic acid, t16:1n-7, as potential biomarkers of dairy fat intake, with incident type 2 diabetes (T2D). Methods and findings Sixteen prospective cohorts from 12 countries (7 from the United States, 7 from Europe, 1 from Australia, 1 from Taiwan) performed new harmonised individual-level analysis for the prospective associations according to a standardised plan. In total, 63,682 participants with a broad range of baseline ages and BMIs and 15,180 incident cases of T2D over the average of 9 years of follow-up were evaluated. Study-specific results were pooled using inverse-variance–weighted meta-analysis. Prespecified interactions by age, sex, BMI, and race/ethnicity were explored in each cohort and were meta-analysed. Potential heterogeneity by cohort-specific characteristics (regions, lipid compartments used for fatty acid assays) was assessed with metaregression. After adjustment for potential confounders, including measures of adiposity (BMI, waist circumference) and lipogenesis (levels of palmitate, triglycerides), higher levels of 15:0, 17:0, and t16:1n-7 were associated with lower incidence of T2D. In the most adjusted model, the hazard ratio (95% CI) for incident T2D per cohort-specific 10th to 90th percentile range of 15:0 was 0.80 (0.73–0.87); of 17:0, 0.65 (0.59–0.72); of t16:1n7, 0.82 (0.70–0.96); and of their sum, 0.71 (0.63–0.79). In exploratory analyses, similar associations for 15:0, 17:0, and the sum of all three fatty acids were present in both genders but stronger in women than in men (pinteraction < 0.001). Whereas studying associations with biomarkers has several advantages, as limitations, the biomarkers do not distinguish between different food sources of dairy fat (e.g., cheese, yogurt, milk), and residual confounding by unmeasured or imprecisely measured confounders may exist. Conclusions In a large meta-analysis that pooled the findings from 16 prospective cohort studies, higher levels of 15:0, 17:0, and t16:1n-7 were associated with a lower risk of T2D., Fumiaki Imamura and colleagues reveal a correlation between higher levels of circulating and adipose odd-chain fatty and trans-palmitoleic acids and lower risk of developing diabetes., Author summary Why was this study done? Effects of dairy fat on type 2 diabetes (T2D) are not well established. While dairy fat contains palmitic acid that could increase risk of T2D, it also contains several other types of fatty acids and further reflects specific foods, such as cheese or yogurt, that could reduce risk. Most prior studies of dairy foods and T2D have relied on self-reported dietary questionnaires, which may have errors or bias in memory as well as challenges in assessing less apparent sources of dairy fat such as in creams, sauces, cheeses, and cooking fats in mixed meals and prepared foods. Circulating and tissue biomarker concentrations of odd-chain saturated fats (15:0, 17:0) and natural ruminant trans-fats (trans-16:1n7) at least partly reflect dairy fat consumption, help capture multiple dietary sources without relying on memory or subjective reporting, and reflect a complementary approach to investigate associations with T2D. A consortium strategy combining all available studies maximises statistical power and generalizability, allows standardised analytical approaches and methods including of key population subgroups, and minimises potential for publication bias. What did the researchers do and find? We conducted a consortium project to pool new participant-level analyses of 16 cohort studies as part of the Fatty Acids and Outcomes Research Consortium (FORCE), including a total of 63,682 adults free of T2D at baseline, among whom 15,158 developed incident T2D over up to 20 years of follow-up. Participating studies conducted standardised analysis of the prospective associations between fatty acid biomarkers (15:0, 17:0, trans-16:1n7, and their sum) and the risk of developing T2D. Pooling all studies, each of the biomarkers and their sum were associated with lower risk of developing T2D, independently of major risk factors for T2D, including age, sex, race/ethnicity, socioeconomic status, physical activity, and obesity. For example, for the sum of these biomarkers, participants with higher levels experienced 29% (95% CI 21% to 37%) lower risk of T2D than adults with lower levels, comparing between the midpoints of the top fifth and the bottom fifth of concentrations. What do these findings mean? Higher circulating and tissue concentrations of odd-chain saturated fats and a natural ruminant trans-fat are associated with lower risk of T2D. While these biomarkers are known to reflect dairy fat consumption, their levels could also be influenced by other unknown factors. The findings support the need for investigation of determinants of levels of these fatty acids as well as health effects of dairy fat in interventional studies. Despite the several advantages of evaluating fatty acid biomarkers, the results cannot distinguish between different types of dairy foods (e.g., milk, cheese, yogurt, others), which could have differential effects. The findings provide the strongest evidence to date for relationships of these fatty acid biomarkers with T2D, informing the potential health effects and corresponding dietary recommendations for consumption of selected dairy products.

An important question in many biological applications, is to estimate or classify gene activity states (active or inactive) based on genome-wide transcriptomics data. Recently, we proposed a Bayesian method, titled MultiMM, which showed superior results compared to existing methods. In short, MultiMM performed better than existing methods on both simulated and real gene expression data, confirming well-known biological results and yielding better agreement with fluxomics data. Despite these promising results, MultiMM has numerous limitations. First, MultiMM leverages co-regulatory models to improve activity state estimates, but information about co-regulation is incorporated in a manner that assumes that networks are known with certainty. Second, MultiMM assumes that genes that change states in the dataset can be distinguished with certainty from those that remain in one state. Third, the model can be sensitive to extreme measures (outliers) of gene expression. In this manuscript, we propose a modified Bayesian approach, which addresses these three limitations by improving outlier handling and by explicitly modeling network and other uncertainty yielding improved gene activity state estimates when compared to MultiMM.

Standard approaches to evaluate the impact of single nucleotide polymorphisms (SNP) on quantitative phenotypes use linear models. However, these normal-based approaches may not optimally model phenotypes which are better represented by Gaussian mixture distributions (e.g., some metabolomics data). We develop a likelihood ratio test on the mixing proportions of two-component Gaussian mixture distributions and consider more restrictive models to increase power in light of a priori biological knowledge. Data were simulated to validate the improved power of the likelihood ratio test and the restricted likelihood ratio test over a linear model and a log transformed linear model. Then, using real data from the Framingham Heart Study, we analyzed 20,315 SNPs on chromosome 11, demonstrating that the proposed likelihood ratio test identifies SNPs well known to participate in the desaturation of certain fatty acids. Our study both validates the approach of increasing power by using the likelihood ratio test that leverages Gaussian mixture models, and creates a model with improved sensitivity and interpretability.

The widespread availability of genome sequencing data made possible by way of next-generation technologies has yielded a flood of different gene-based rare variant association tests. Most of these tests have been published because they have superior power for particular genetic architectures. However, for applied researchers it is challenging to know which test to choose in practice when little is known a priori about genetic architecture. Recently, tests have been proposed which combine two particular individual tests (one burden and one variance components) to minimize power loss while improving robustness to a wider range of genetic architectures. In our analysis we propose an expansion of these approaches, yielding a general method that works for combining any number of individual tests. We demonstrate that running multiple different tests on the same data set and using a Bonferroni correction for multiple testing is never better than combining tests using our general method. We also find that using a test statistic that is highly robust to the inclusion of non-causal variants (joint-infinity) together with a previously published combined test (sequence kernel adaptive test-optimal) provides improved robustness to a wide range of genetic architectures and should be considered for use in practice. Software for this approach is supplied. We support the increased use of combined tests in practice - as well as further exploration of novel combined testing approaches using the general framework provided here - to maximize robustness of rare variant testing strategies against a wide range of genetic architectures.

Both metabolomic and genomic approaches are valuable for risk analysis, however typical approaches evaluating differences in means do not model the changes well. Gene polymorphisms that alter function would appear as distinct populations, or metabotypes, from the predominant one, in which case risk is revealed as changed mixing proportions between control and case samples. Here we validate a model accounting for mixed populations using biomarkers of fatty acid metabolism derived from a case/control study of acute coronary syndrome subjects in which both metabolomic and genomic approaches have been used previously. We first used simulated data to show improved power and sensitivity in the approach compared to classic approaches. We then used the metabolic biomarkers to test for evidence of distinct metabotypes and different proportions among cases and controls. In simulation, our model outperformed all other approaches including Mann–Whitney, t tests, and χ2. Using real data, we found distinct metabotypes of six of the seven activities tested, and different mixing proportions in five of the six activity biomarkers: D9D, ELOVL6, ELOVL5, FADS1, and Sprecher pathway chain shortening (SCS). High activity metabotypes of non-essential fatty acids and SCS decreased odds for acute coronary syndrome, however high activity metabotypes of 20-carbon fatty acid synthesis increased odds. Our study validates an approach that accounts for both metabolomic and genomic theory by demonstrating improved sensitivity and specificity, better performance in real world data, and more straightforward interpretability.

Prolonged, severe, unalleviated fatigue may be disabling whether it occurs on its own or in conjunction with medical or psychiatric conditions. This paper compares the prevalence and correlates of prolonged fatigue in general population samples in Ukraine versus the U.S.Population surveys were conducted in 2002 in both Ukraine (Ukraine World Mental Health [WMH] Survey) and the U.S. (National Comorbidity Survey-Replication; NCS-R). Both surveys administered the Composite International Diagnostic Interview (CIDI 3.0), which contained modules assessing: neurasthenia (prolonged fatigue); mood, anxiety, and alcohol/drug use disorders; chronic medical conditions; and demographic characteristics. Multivariable logistic regression was used to examine risk factors in each country.The lifetime prevalence of prolonged fatigue was higher in Ukraine (5.2%) than the U.S. (3.7%). In both countries, one-fifth of individuals with prolonged fatigue had no medical or DSM-IV psychiatric condition. Also in both settings, fatigue was significantly associated with sociodemographic characteristics (being female, not working, and married before) as well as early onset and adult episodes of mood/anxiety disorder. Fatigue prevalence in Ukraine increased with age, but decreased in the U.S. at age 70. Unique risk factors for fatigue in Ukraine included lower socio-economic status, Ukrainian vs Russian ethnicity, and cardiovascular disease. Unique risk factors in the U.S. were parental depression/anxiety, adult episodes of alcohol/drugs, pain conditions, and other health problems.The lifetime prevalence of prolonged fatigue in Ukraine was 40% higher than that found in U.S. data. In addition, fatigue prevalence increased sharply with age in Ukraine perhaps due to limited social and medical resources and greater comorbidity.

To date, gene-based rare variant testing approaches have focused on aggregating information across sets of variants to maximize statistical power in identifying genes showing significant association with diseases. Beyond identifying genes that are associated with diseases, the identification of causal variant(s) in those genes and estimation of their effect is crucial for planning replication studies and characterizing the genetic architecture of the locus. However, we illustrate that straightforward single-marker association statistics can suffer from substantial bias introduced by conditioning on gene-based test significance, due to the phenomenon often referred to as “winner's curse.” We illustrate the ramifications of this bias on variant effect size estimation and variant prioritization/ranking approaches, outline parameters of genetic architecture that affect this bias, and propose a bootstrap resampling method to correct for this bias. We find that our correction method significantly reduces the bias due to winner's curse (average two-fold decrease in bias, p < 2.2 × 10−6) and, consequently, substantially improves mean squared error and variant prioritization/ranking. The method is particularly helpful in adjustment for winner's curse effects when the initial gene-based test has low power and for relatively more common, non-causal variants. Adjustment for winner's curse is recommended for all post-hoc estimation and ranking of variants after a gene-based test. Further work is necessary to continue seeking ways to reduce bias and improve inference in post-hoc analysis of gene-based tests under a wide variety of genetic architectures.

Dog ownership has been associated with increased physical activity in the general adult population.The objective of this study was to examine dog ownership and dog walking and their relationship with home-based and phase II cardiac rehabilitation exercise, depression, and hopelessness in patients with ischemic heart disease.A total of 122 patients with ischemic heart disease were included in this prospective observational study. Patients completed dog ownership/walking questions during their hospitalization. The Cardiac Rehabilitation Exercise Participation Tool, Patient Health Questionnaire-9, and State-Trait Hopelessness Scale were completed by mail at 3, 8, or 12 months later. Regression modeling was used to evaluate the significance of dog ownership/walking on exercise, depression and hopelessness.The sample was 34.4% female and had a mean age of 64.7 ± 9.1 years. Forty-two patients (34.4%) reported owning a dog. Patients who owned but did not walk their dog reported significantly lower levels of home exercise compared with patients who walked their dogs at least 1 day per week (36.8% for non-dog walkers vs 73.9% for dog walkers, P = .019). The odds of participating in home exercise were significantly higher for dog walkers compared with non-dog walkers (odds ratio, 8.1 [1.7, 38.5] vs 1.0). There were no differences in phase II cardiac rehabilitation exercise, depression, or hopelessness between dog owners and non-dog owners or between dog walkers and non-dog walkers.These findings show a beneficial effect on home-based exercise for those who dog-walk at least 1 day per week. Healthcare professionals should encourage dog walking to increase dog owners' physical activity levels.

Introduction: Hopelessness is associated with increased adverse events and decreased survival in patients with coronary heart disease (CHD). Hopelessness can persist in these patients and reduce their participation in hospital-based cardiac rehabilitation (CR) exercise following an acute event. Because the majority of CHD patients do not attend a hospital-based CR exercise program, examination of factors affecting home exercise is needed. The purpose of this study was to describe the impact of hopelessness levels on both home- and hospital based CR exercise participation in patients with CHD. Hypothesis: It was hypothesized that higher state and trait hopelessness levels would adversely affect both home- and hospital-based CR exercise participation. Methods: The Theory of Hopelessness Depression was used as a foundation for study aims. Using a descriptive, longitudinal design, 282 patients who had been hospitalized with a CHD event were asked to complete the State-Trait Hopelessness Scale (STHS) during their hospitalization and the STHS and the Cardiac Rehabilitation Exercise Participation Questionnaire at 3, 8, and 12 months after hospital discharge. Patients who provided data at any two concurrent time points over the year were included in the analyses. Regular exercise was defined as walking or biking ≥3 days/week in a home- or hospital-based Phase II CR exercise program. Logistic regression was used to evaluate the relationship between STHS scores on the likelihood that patients would participate in regular exercise in home- or hospital-based Phase II CR settings. Results: Patients were predominantly male (64.9%) with a mean age of 65.4±9.7 years. Patients had persistent, modest levels of state and trait hopelessness across all time points. High levels of state and trait hopelessness were predictive of lower home-based exercise participation (state: OR 0.4, 95% CI [0.1, 0.7], p=0.002; trait: OR 0.4, 95% CI [0.2, 0.8], p=0.01) but not hospital-based Phase II CR exercise, after adjusting for age and sex. Conclusions: These findings demonstrate the importance of assessing hopelessness in patients with CHD and provide critical evidence of the need for clinicians to encourage CHD patients who are feeling hopeless to participate in CR exercise, particularly in the home setting.

Background: Circulating saturated fatty acids are biomarkers of diet and metabolism that may influence the pathogenesis of diabetes. Unlike palmitic acid (16:0), which has been extensively studied, little is known of the relationship of very long-chain saturated fatty acids (VLSFAs), with 20 carbons or more, to diabetes risk. Objective: To investigate the associations of circulating levels of VLSFA with incident diabetes. Methods: A meta-analysis was conducted within a consortium of prospective (cohort or nested case-control) studies having circulating measures of one or more VLSFAs, including arachidic acid (20:0), behenic acid (22:0) and lignoceric acid (24:0). Standardized analysis was conducted in each study using pre-specified models, exposures, outcomes, and covariates. Study-specific estimates were pooled using fixed effects meta-analysis. Results: Current findings were based on 9 participating studies, including 46,549 total participants and 13,750 incident diabetes. In multivariable-adjusted analyses, higher levels of all 3 VLSFAs were associated with lower risk of incident diabetes. Pooled RRs (95% CI) per interquintile range were 0.80 (0.71-0.90) for 20:0; 0.83 (0.76-0.91) for 22:0; and 0.70 (0.63-0.79) for 24:0, after adjustment for demographics, lifestyle factors and clinical conditions. Additional adjustments for circulating palmitic acid and triglyceride levels moved the RRs toward the null (illustrated for 24:0, in model 3 of the Figure ). Conclusions: Based on meta-analysis of results from several studies around the world, biomarker levels of VLSFA are associated with lower risk of incident diabetes, potentially mediated by effects on circulating triglycerides and 16:0.

Introduction: Dog ownership and dog walking have been associated with increased physical activity in the general population. Although evidence suggests an association between pet ownership and increased survival in patients with coronary heart disease (CHD), little is known about how dog ownership and dog walking may be associated with exercise habits in CHD patients. Hypothesis: The purpose of this study was to examine dog ownership and dog walking and their relationship with frequency of home- and hospital-based CR exercise in patients with CHD. It was hypothesized that CHD patients who walk their dogs would report more frequent home- and hospital-based CR exercise. Methods: The study was based on Self-Determination Theory. A prospective observational design was used. A total of 122 patients with CHD completed a dog ownership and walking survey during their hospitalization and were asked to complete the Cardiac Rehabilitation Exercise Participation Tool by mail at 3, 8 and 12 months later. Patients self-selected whether they walked or biked in a home- or hospital-based Phase II CR exercise setting and self-reported number of days per week of exercise in each setting. Results: The sample was predominantly male (n=82; 67.2%) with a mean age of 64.7±9.1 years. Forty-two patients (34.4%) reported owning a dog. There were no differences in participation in home or Phase II CR exercise in dog owners versus non-dog owners (home CR: 57.1% vs. 62.5%, p=0.57 and Phase II CR: 31.0% vs. 32.5%, p=0.86). Among dog owners, 23 (54.8%) reported walking their dog at least 1 day/week. There were no significant differences in Phase II CR exercise among non-dog owners, dog owners who did not dog walk, and those who walked their dogs at least 1 day/week (owners/walkers: 34.8%, owners/non-walkers: 26.3%, non-owners: 32.5%; p=0.83). However, patients who owned but did not walk their dog reported significantly lower levels of home exercise compared to patients who owned and walked their dogs at least 1 day/week (owners/non-walkers: 36.8% vs. owners/walkers: 73.9%, p=0.019) and compared to non-dog owners (owners/non-walkers: 36.8% vs. non-owners: 62.5%; p=0.047). Conclusions: Results suggest that dog ownership is not equivalent to dog walking when examining exercise frequency in CHD patients. Dog owners were no more likely to exercise than non-dog owners. However, findings show a beneficial effect on home-based exercise for CHD patients who walk their dogs at least one day a week. Healthcare professionals should encourage CHD patients who are dog owners to walk their dogs as a strategy to increase home-based exercise.

When analyzing family data, we dream of perfectly informative data, even whole-genome sequences (WGSs) for all family members. Reality intervenes, and we find that next-generation sequencing (NGS) data have errors and are often too expensive or impossible to collect on everyone. The Genetic Analysis Workshop 18 working groups on quality control and dropping WGSs through families using a genome-wide association framework focused on finding, correcting, and using errors within the available sequence and family data, developing methods to infer and analyze missing sequence data among relatives, and testing for linkage and association with simulated blood pressure. We found that single-nucleotide polymorphisms, NGS data, and imputed data are generally concordant but that errors are particularly likely at rare variants, for homozygous genotypes, within regions with repeated sequences or structural variants, and within sequence data imputed from unrelated individuals. Admixture complicated identification of cryptic relatedness, but information from Mendelian transmission improved error detection and provided an estimate of the de novo mutation rate. Computationally, fast rule-based imputation was accurate but could not cover as many loci or subjects as more computationally demanding probability-based methods. Incorporating population-level data into pedigree-based imputation methods improved results. Observed data outperformed imputed data in association testing, but imputed data were also useful. We discuss the strengths and weaknesses of existing methods and suggest possible future directions, such as improving communication between data collectors and data analysts, establishing thresholds for and improving imputation quality, and incorporating error into imputation and analytical models.

Chronic pain can pose a serious challenge in everyday life for many individuals globally, especially in developing countries, but studies explicitly exploring risk factors of chronic pain beyond demographic characteristics using survey data have been scarce. To address this problem, this study analyzed World Health Organization data on chronic pain in Ukraine to explore demographic, psychological, and treatment perception-related risk factors to chronic pain. We replicated previous reports of older age, female sex, married status, inadequate financial resources, and comorbidity of other physical conditions as significant demographic risk factors for chronic pain diagnosis but not necessarily for severe pain. We also found evidence for psychological risk factors and treatment perceptions as significant predictors for chronic pain diagnosis and its severity. These results provide a first step in examining beyond demographic risk factors for chronic pain diagnosis and severity and, instead, assessing potential psychological risk factors.

Background: The prognostic value of erythrocyte levels of n-6 fatty acids (FAs) for total mortality and cardiovascular disease (CVD) outcomes remains an open question. Methods: We examined cardiovascular (CV) outcomes and death in 2500 individuals in the Framingham Heart Study Offspring cohort without prevalent CVD (mean age 66 years, 57% women) as a function of baseline levels of different length n-6 FAs (18 carbon, 20 carbon, and 22 carbon) in the erythrocyte membranes. Clinical outcomes were monitored for up to 9.5 years (median follow up, 7.26 years). Cox proportional hazards models were adjusted for a variety of demographic characteristics, clinical status, and red blood cell (RBC) n-6 and long chain n-3 FA content. Results: There were 245 CV events, 119 coronary heart disease (CHD) events, 105 ischemic strokes, 58 CVD deaths, and 350 deaths from all causes. Few associations between either mortality or CVD outcomes were observed for n-6 FAs, with those that were observed becoming non-significant after adjusting for n-3 FA levels. Conclusions: Higher circulating levels of marine n-3 FA levels are associated with reduced risk for incident CVD and ischemic stroke and for death from CHD and all-causes, however, in the same sample little evidence exists for association with n-6 FAs. Further work is needed to identify a full profile of FAs associated with cardiovascular risk and mortality.

Hopelessness is predictive in the development of coronary heart disease (CHD) and can persist in patients after a CHD event, adversely affecting recovery. Hopelessness may represent a temporary response (state) or a chronic outlook (trait). Common hopelessness measures fail to differentiate state from trait hopelessness, a potentially important differentiation for treatment. The State–Trait Hopelessness Scale (STHS) was developed and pilot tested with two groups of college students ( n = 39 and 190) and patients with CHD ( n = 44). The instrument was then used with 520 patients, confirming reliability (Cronbach’s α) for the State (.88) and Trait (.91) subscales and concurrent and predictive validity. Separate exploratory factor analyses showed two factors (hopelessness present or hopelessness absent) for the State and Trait subscales, accounting for 58.9% and 57.3% of variance, respectively. These findings support future use of the tool in clinical settings and in intervention studies focused on hopelessness.

The wave of next-generation sequencing data has arrived. However, many questions still remain about how to best analyze sequence data, particularly the contribution of rare genetic variants to human disease. Numerous statistical methods have been proposed to aggregate association signals across multiple rare variant sites in an effort to increase statistical power; however, the precise relation between the tests is often not well understood. We present a geometric representation for rare variant data in which rare allele counts in case and control samples are treated as vectors in Euclidean space. The geometric framework facilitates a rigorous classification of existing rare variant tests into two broad categories: tests for a difference in the lengths of the case and control vectors, and joint tests for a difference in either the lengths or angles of the two vectors. We demonstrate that genetic architecture of a trait, including the number and frequency of risk alleles, directly relates to the behavior of the length and joint tests. Hence, the geometric framework allows prediction of which tests will perform best under different disease models. Furthermore, the structure of the geometric framework immediately suggests additional classes and types of rare variant tests. We consider two general classes of tests which show robustness to noncausal and protective variants. The geometric framework introduces a novel and unique method to assess current rare variant methodology and provides guidelines for both applied and theoretical researchers.

Objective: The use of haplotypes to impute the genotypes of unmeasured single nucleotide variants continues to rise in popularity. Simulation results suggest that the use of the dosage as a one-dimensional summary statistic of imputation posterior probabilities may be optimal both in terms of statistical power and computational efficiency; however, little theoretical understanding is available to explain and unify these simulation results. In our analysis, we provide a theoretical foundation for the use of the dosage as a one-dimensional summary statistic of genotype posterior probabilities from any technology. Methods: We analytically evaluate the dosage, mode and the more general set of all one-dimensional summary statistics of two-dimensional (three posterior probabilities that must sum to 1) genotype posterior probability vectors. Results: We prove that the dosage is an optimal one-dimensional summary statistic under a typical linear disease model and is robust to violations of this model. Simulation results confirm our theoretical findings. Conclusions: Our analysis provides a strong theoretical basis for the use of the dosage as a one-dimensional summary statistic of genotype posterior probability vectors in related tests of genetic association across a wide variety of genetic disease models.