In genome-wide association studies (GWAS), "generalization" is the replication of genotype-phenotype association in a population with different ancestry than the population in which it was first ...identified. Current practices for declaring generalizations rely on testing associations while controlling the family-wise error rate (FWER) in the discovery study, then separately controlling error measures in the follow-up study. This approach does not guarantee control over the FWER or false discovery rate (FDR) of the generalization null hypotheses. It also fails to leverage the two-stage design to increase power for detecting generalized associations. We provide a formal statistical framework for quantifying the evidence of generalization that accounts for the (in)consistency between the directions of associations in the discovery and follow-up studies. We develop the directional generalization FWER (FWER
) and FDR (FDR
) controlling r-values, which are used to declare associations as generalized. This framework extends to generalization testing when applied to a published list of Single Nucleotide Polymorphism-(SNP)-trait associations. Our methods control FWER
or FDR
under various SNP selection rules based on P-values in the discovery study. We find that it is often beneficial to use a more lenient P-value threshold than the genome-wide significance threshold. In a GWAS of total cholesterol in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), when testing all SNPs with P-values <5×10-8 (15 genomic regions) for generalization in a large GWAS of whites, we generalized SNPs from 15 regions. But when testing all SNPs with P-values <6.6×10-5 (89 regions), we generalized SNPs from 27 regions.
It is unclear whether testing for novel risk factors, such as a cardiovascular genetic risk score (cGRS), improves clinical decision making or health outcomes when used for targeting statin ...initiation in the primary prevention of atherosclerotic cardiovascular disease (ASCVD). Our objective was to estimate the cost-effectiveness of cGRS testing to inform clinical decision making about statin initiation in individuals with low-to-intermediate (2.5%-7.5%) 10-year predicted risk of ASCVD.
We evaluated the cost-effectiveness of testing for a 27-single-nucleotide polymorphism cGRS comparing 4 test/treat strategies: treat all, treat none, test/treat if cGRS is high, and test/treat if cGRS is intermediate or high. We tested a set of clinical scenarios of men and women, aged 45 to 65 years, with 10-year ASCVD risks between 2.5% and 7.5%. Our primary outcome measure was cost per quality-adjusted life-year gained. Under base case assumptions for statin disutility and cost, the preferred strategy is to treat all patients with ASCVD risk >2.5% without cGRS testing. For certain clinical scenarios, such as a 57-year-old man with a 10-year ASCVD risk of 7.5%, cGRS testing can be cost-effective under a limited set of assumptions; for example, when statins cost $15 per month and statin disutility is 0.013 (ie, willing to trade 3 months of life in perfect health to avoid 20 years of statin therapy), the preferred strategy (using a willingness-to-pay threshold of $50 000 per quality-adjusted life-year gained) is to test and treat if cGRS is intermediate or high. Overall, the results were not sensitive to assumptions about statin efficacy and harms.
Testing for a 27-single-nucleotide polymorphism cGRS is generally not a cost-effective approach for targeting statin therapy in the primary prevention of ASCVD for low- to intermediate-risk patients.
Mitigating age-related disease and disability presents challenges. Physical activity (PA) may be influential for prolonging health and functioning, warranting characterization of its patterns over ...the life course in population-based data. With the availability of up to three self-reported assessments of past year leisure-time PA (LTPA) over multiple decades in 15,036 participants (26% African American; 55% women; mean baseline age=54; median follow-up=23 years) from the Atherosclerosis Risk in Communities (ARIC) Study sampled from four U.S. communities, race-sex-stratified trajectories of average weekly intensity (metabolic equivalent of task (MET)), duration (hours), and energy expenditure or volume (MET-h) of LTPA were developed from age 45 to 90 using joint models to accommodate expected non-ignorable attrition. Declines in weekly LTPA intensity, duration, and volume from age 70 to 90 were observed in white women (2.9 to 1.2 MET; 2.5 to 0.6 h; 11.1 to 2.6 MET-h), white men (2.5 to 1.0 MET; 3.5 to 1.8 h; 15.5 to 6.4 MET-h), African American women (2.5 to 2.4 MET; 0.8 to 0.1 h; 6.7 to 6.0 MET-h), and African American men (2.3 to 1.4 MET; 1.5 to 0.6 h; 8.0 to 2.3 MET-h). These data reveal population-wide shifts towards less active lifestyles in older adulthood.
loss-of-function (LOF) variants allow for the examination of the effects of lifetime reduced low-density lipoprotein cholesterol (LDL-C) on cardiovascular events. We examined the association of
LOF ...variants with LDL-C and incident coronary heart disease and stroke through a meta-analysis of data from 8 observational cohorts and 1 randomized trial of statin therapy.
These 9 studies together included 17 459 blacks with 403 (2.3%) having at least 1 Y142X or C679X variant and 31 306 whites with 955 (3.1%) having at least 1 R46L variant. Unadjusted odds ratios for associations between
LOF variants and incident coronary heart disease (851 events in blacks and 2662 events in whites) and stroke (523 events in blacks and 1660 events in whites) were calculated using pooled Mantel-Haenszel estimates with continuity correction factors. Pooling results across studies using fixed-effects inverse-variance-weighted models,
LOF variants were associated with 35 mg/dL (95% confidence interval CI, 32-39) lower LDL-C in blacks and 13 mg/dL (95% CI, 11-16) lower LDL-C in whites.
LOF variants were associated with a pooled odds ratio for coronary heart disease of 0.51 (95% CI, 0.28-0.92) in blacks and 0.82 (95% CI, 0.63-1.06) in whites.
LOF variants were not associated with incident stroke (odds ratio, 0.84; 95% CI, 0.48-1.47 in blacks and odds ratio, 1.06; 95% CI, 0.80-1.41 in whites).
LOF variants were associated with lower LDL-C and coronary heart disease incidence.
LOF variants were not associated with stroke risk.
Concurrent variation in adiposity and inflammation suggests potential shared functional pathways and pleiotropic disease underpinning. Yet, exploration of pleiotropy in the context of ...adiposity-inflammation has been scarce, and none has included self-identified Hispanic/Latino populations. Given the high level of ancestral diversity in Hispanic American population, genetic studies may reveal variants that are infrequent/monomorphic in more homogeneous populations.
Using multi-trait Adaptive Sum of Powered Score (aSPU) method, we examined individual and shared genetic effects underlying inflammatory (CRP) and adiposity-related traits (Body Mass Index BMI), and central adiposity (Waist to Hip Ratio WHR) in HLA participating in the Population Architecture Using Genomics and Epidemiology (PAGE) cohort (N = 35,871) with replication of effects in the Cameron County Hispanic Cohort (CCHC) which consists of Mexican American individuals.
Of the > 16 million SNPs tested, variants representing 7 independent loci were found to illustrate significant association with multiple traits. Two out of 7 variants were replicated at statistically significant level in multi-trait analyses in CCHC. The lead variant on APOE (rs439401) and rs11208712 were found to harbor multi-trait associations with adiposity and inflammation.
Results from this study demonstrate the importance of considering pleiotropy for improving our understanding of the etiology of the various metabolic pathways that regulate cardiovascular disease development.
Background Evidence shows that dietary factors play an important role in blood pressure. However, there is no clear understanding of whether hypertension diagnosis is associated with dietary ...modifications. The aim of this study is to estimate the longitudinal association between hypertension diagnosis and subsequent changes (within 2-4 years) in dietary sodium, potassium, and sodium-potassium (Na/K) ratio. Methods and Results We included adults (18-75 years, n=16 264) from up to 9 waves (1991-2015) of the China Health and Nutrition Survey. Diet data were collected using three 24-hour dietary recalls and a household food inventory. We used fixed-effects models to estimate the association between newly self-reported diagnosed hypertension and subsequent within-individual changes in sodium, potassium, and Na/K ratio. We also examined changes among couples and at the household level. Results suggest that on average, men who were diagnosed with hypertension decreased their sodium intake by 251 mg/d and their Na/K ratio by 0.19 within 2 to 4 years after diagnosis (
<0.005). Among spouse pairs, sodium intake and Na/K ratio of women decreased when their husbands were diagnosed (
<0.05). Household average sodium density and Na/K ratio decreased, and household average potassium density increased after a man was diagnosed. In contrast, changes were not statistically significant when women were diagnosed. Conclusions Our findings suggest that hypertension diagnosis for a man may result in modest dietary improvements for him, his wife, and other household members. Yet, diagnosis for a woman does not seem to result in dietary changes for her or her household members.
Heart disease and cancer are the 2 major diseases associated with mortality risk in the United States. Four decades of improvements in heart disease mortality slowed after 2011; this slowing has been ...associated with the obesity epidemic. The same pattern has not been observed for total cancer mortality. However, trends in total cancer mortality may obscure patterns specific to obesity-associated cancers.
To investigate whether trends in obesity-associated cancer mortality mirror the slowed mortality improvements observed for heart disease associated with the obesity epidemic.
This cross-sectional study compared US mortality trends for International Statistical Classification of Diseases and Related Health Problems, Tenth Revision-defined cancer (total cancer, obesity-associated cancer, and cancer not associated with obesity) and heart disease deaths from January 1, 1999, to December 31, 2018. Data were included on decedents with complete information on the underlying cause of death, age, sex, race, and ethnicity.
Changes in age-adjusted cause-specific mortality rates between 1999-2011 and 2011-2018 were compared.
Annual relative rates of change in age-adjusted mortality rates (AAMRs) in the overall population and stratified by sex, race, and ethnicity were estimated using Poisson regression. Differences in AAMR annual relative rates of change before and after 2011 were evaluated using Wald tests.
A total of 50 163 483 decedents met the inclusion criteria (50.1% female decedents, 79.9% non-Hispanic White decedents, and 11.7% non-Hispanic Black decedents; mean SD age, 72.8 18.5 years). In contrast with heart disease mortality, for which improvements slowed between 1999-2011 and 2011-2018, decreases in total cancer AAMR relative change accelerated between 1999-2011 (-1.48 95% CI, -1.43 to -1.52) and 2011-2018 (-1.77 95% CI, -1.67 to -1.86) (P < .001). For obesity-associated cancer mortality, which accounted for approximately 33% of total cancer deaths annually, decreases in annual AAMR relative change decelerated from -1.19 (95% CI, -1.13 to -1.26) in 1999-2011 to -0.83 (95% CI, -0.70 to -0.96) in 2011-2018 (P < .001). The largest decelerations in obesity-associated cancer mortality were observed for female decedents (-1.45 95% CI, -1.36 to -1.53 in 1999-2011 and -0.91 95% CI, -0.75 to -1.07 in 2011-2018; P < .001) and non-Hispanic White individuals (-1.16 95% CI, -1.09 to -1.22 in 1999-2011 and -0.68 95% CI, -0.55 to -0.81 in 2011-2018; P < .001).
Slowing improvements in obesity-associated cancer mortality were obscured when considering total cancer mortality. These findings potentially signal a changing profile of cancer-associated mortality that may parallel trends previously observed for heart disease as the consequences of the obesity epidemic are understood.
Mendelian randomization has been widely used to assess the causal effect of a heritable exposure variable on an outcome of interest, using genetic variants as instrumental variables. In practice, ...data on the exposure variable can be incomplete due to high cost of measurement and technical limits of detection. In this paper, we propose a valid and efficient method to handle both unmeasured and undetectable values of the exposure variable in one-sample Mendelian randomization analysis with individual-level data. We estimate the causal effect of the exposure variable on the outcome using maximum likelihood estimation and develop an expectation-maximization algorithm for the computation of the estimator. Simulation studies show that the proposed method performs well in making inference on the causal effect. We apply our method to the Hispanic Community Health Study/Study of Latinos, a community-based prospective cohort study, and estimate the causal effect of several metabolites on phenotypes of interest.
We consider Mendelian randomization with individual-level data where the exposure is potentially unmeasured and undetectable. We perform maximum likelihood estimation of the causal effect through an expectation-maximization algorithm. We demonstrate the usefulness of our methods through simulated and empirical data.
Background Excess adiposity, which affects 69% of US adults, increases coronary heart disease (CHD) risk in an association that manifests below conventional obesity cut points. The population-level ...impact on CHD risk that is attainable through modest adiposity reductions in populations is not well characterized. We estimated the effect of hypothetical reductions in both body mass index (BMI) and waist circumference (WC) on CHD incidence. Methods and Results The study population included 13 610 ARIC (Atherosclerosis Risk in Communities) participants. Our hypothetical reduction in BMI or WC was applied relative to the temporal trend, with no hypothetical reduction among those with BMI >24 or WC >88 cm, respectively. This threshold for hypothetical reduction is near the clinical guidelines for excess adiposity. CHD risk differences compared the hypothetical reduction with no reduction. Sensitivity analysis was conducted to estimate the effect of applying the hypothetical BMI reduction at the established overweight cut point of 25. Cumulative 12-year CHD incidence with no intervention was 6.3% (95% CI, 5.9-6.8%). Risk differences following the hypothetical BMI and WC reductions were -0.6% (95% CI, -1.0% to -0.1%) and -1.0% (95% CI, -1.4% to -0.5%), respectively. These results were robust for the sensitivity analyses. Consequently, we estimated that this hypothetical reduction of 5% in BMI and WC, respectively, could have prevented 9% and 16%, respectively, of the CHD events occurring in this study population over 12 years, after adjustment for established CHD risk factors. Conclusions Meaningful CHD risk reductions could derive from modest reductions in adiposity attainable through lifestyle modification.
Thousands of genetic variants have been associated with hematological traits, though target genes remain unknown at most loci. Moreover, limited analyses have been conducted in African ancestry and ...Hispanic/Latino populations; hematological trait associated variants more common in these populations have likely been missed.
To derive gene expression prediction models, we used ancestry-stratified datasets from the Multi-Ethnic Study of Atherosclerosis (MESA, including
= 229 African American and
= 381 Hispanic/Latino participants, monocytes) and the Depression Genes and Networks study (DGN,
= 922 European ancestry participants, whole blood). We then performed a transcriptome-wide association study (TWAS) for platelet count, hemoglobin, hematocrit, and white blood cell count in African (
= 27,955) and Hispanic/Latino (
= 28,324) ancestry participants.
Our results revealed 24 suggestive signals (
< 1 × 10
) that were conditionally distinct from known GWAS identified variants and successfully replicated these signals in European ancestry subjects from UK Biobank. We found modestly improved correlation of predicted and measured gene expression in an independent African American cohort (the Genetic Epidemiology Network of Arteriopathy (GENOA) study (
= 802), lymphoblastoid cell lines) using the larger DGN reference panel; however, some genes were well predicted using MESA but not DGN.
These analyses demonstrate the importance of performing TWAS and other genetic analyses across diverse populations and of balancing sample size and ancestry background matching when selecting a TWAS reference panel.
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