Collaborative Cohort of Cohorts for COVID-19 Research (C4R) Study: Study Design.

The Collaborative Cohort of Cohorts for COVID-19 Research (C4R) is a national prospective study of adults comprising 14 established US prospective cohort studies. Starting as early as 1971, investigators in the C4R cohort studies have collected data on clinical and subclinical diseases and their risk factors, including behavior, cognition, biomarkers, and social determinants of health. C4R links this pre-coronavirus disease 2019 (COVID-19) phenotyping to information on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and acute and postacute COVID-related illness. C4R is largely population-based, has an age range of 18-108 years, and reflects the racial, ethnic, socioeconomic, and geographic diversity of the United States. C4R ascertains SARS-CoV-2 infection and COVID-19 illness using standardized questionnaires, ascertainment of COVID-related hospitalizations and deaths, and a SARS-CoV-2 serosurvey conducted via dried blood spots. Master protocols leverage existing robust retention rates for telephone and in-person examinations and high-quality event surveillance. Extensive prepandemic data minimize referral, survival, and recall bias. Data are harmonized with research-quality phenotyping unmatched by clinical and survey-based studies; these data will be pooled and shared widely to expedite collaboration and scientific findings. This resource will allow evaluation of risk and resilience factors for COVID-19 severity and outcomes, including postacute sequelae, and assessment of the social and behavioral impact of the pandemic on long-term health trajectories.

Knowledge Gaps, Challenges, and Opportunities in Health and Prevention Research for Asian Americans, Native Hawaiians, and Pacific Islanders: A Report From the 2021 National Institutes of Health Workshop.

Asian Americans (AsA), Native Hawaiians, and Pacific Islanders (NHPI) comprise 7.7% of the U.S. population, and AsA have had the fastest growth rate since 2010. Yet the National Institutes of Health (NIH) has invested only 0.17% of its budget on AsA and NHPI research between 1992 and 2018. More than 40 ethnic subgroups are included within AsA and NHPI (with no majority subpopulation), which are highly diverse culturally, demographically, linguistically, and socioeconomically. However, data for these groups are often aggregated, masking critical health disparities and their drivers. To address these issues, in March 2021, the National Heart, Lung, and Blood Institute, in partnership with 8 other NIH institutes, convened a multidisciplinary workshop to review current research, knowledge gaps, opportunities, barriers, and approaches for prevention research for AsA and NHPI populations. The workshop covered 5 domains: 1) sociocultural, environmental, psychological health, and lifestyle dimensions; 2) metabolic disorders; 3) cardiovascular and lung diseases; 4) cancer; and 5) cognitive function and healthy aging. Two recurring themes emerged: Very limited data on the epidemiology, risk factors, and outcomes for most conditions are available, and most existing data are not disaggregated by subgroup, masking variation in risk factors, disease occurrence, and trajectories. Leveraging the vast phenotypic differences among AsA and NHPI groups was identified as a key opportunity to yield novel clues into etiologic and prognostic factors to inform prevention efforts and intervention strategies. Promising approaches for future research include developing collaborations with community partners, investing in infrastructure support for cohort studies, enhancing existing data sources to enable data disaggregation, and incorporating novel technology for objective measurement. Research on AsA and NHPI subgroups is urgently needed to eliminate disparities and promote health equity in these populations.

Funding of Hispanic/Latino Health-Related Research by the National Institutes of Health: An Analysis of the Portfolio of Research Program Grants on Six Health Topic Areas.

Hispanics/Latinos are expected to constitute 25% of the U.S. population by 2060. Differences in the prevalence of health risk factors, chronic diseases, and access to and utilization of health-care services between Hispanics/Latinos and other populations in the U.S. have been documented. This study aimed to describe and analyze the landscape of Research Program Grants (RPGs) funded by the National Institutes of Health (NIH) between 2008 and 2015 involving Hispanic/Latino health research in six health condition areas-asthma, cancer, dementia, diabetes, liver/gallbladder disease, and obesity-and to identify opportunities for continued research in these areas. Using an NIH internal search engine, we identified new and renewal Hispanic/Latino health RPGs searching for specific Hispanic/Latino identifiers in the Title, Abstract, and Specific Aims. We used descriptive statistics to examine the distribution of funded RPGs by NIH disease-based classification codes for the six health condition areas of interest, and other selected characteristics. The most prominent clusters of research subtopics were identified within each health condition area, and performance sites were mapped at the city level. Within the selected time frame, 3,221 Hispanic/Latino health-related unique RPGs were funded (constituting 4.4% of all funded RPGs), and of those 625 RPGs were eligible for review and coding in the present study. Cancer and obesity were the most commonly studied health condition areas (72%), while studies on mechanisms of disease-biological and non-biological-(72.6%), behavioral research (42.1%) and epidemiological studies (38.1%) were the most common types of research. Most of the primary performance sites were in California, Texas, the northeastern U.S., and Illinois. The predominance of mechanistic, behavioral, and epidemiological studies in our analysis poses opportunities to evaluate knowledge gained and their clinical application, explore new research questions, or to update some methods or instruments. The findings of the present study suggest opportunities to expand research in understudied mechanisms of disease that could explain differences in prevalence of conditions like diabetes and cancer among different heritage groups. In addition, our findings suggest that the impact of interventions or policies designed to reduce health disparities, innovative multi-level interventions, implementation and dissemination studies, the role of health information technology on health outcomes, and the intersectionality of individual, sociocultural, geographic, and other factors on health outcomes, among others, are understudied approaches, which could potentially advance research in Hispanic/Latino health and contribute to the achievement of better health outcomes in this diverse population.

Equalization of four cardiovascular risk algorithms after systematic recalibration: individual-participant meta-analysis of 86 prospective studies.

AIMS: There is debate about the optimum algorithm for cardiovascular disease (CVD) risk estimation. We conducted head-to-head comparisons of four algorithms recommended by primary prevention guidelines, before and after 'recalibration', a method that adapts risk algorithms to take account of differences in the risk characteristics of the populations being studied. METHODS AND RESULTS: Using individual-participant data on 360 737 participants without CVD at baseline in 86 prospective studies from 22 countries, we compared the Framingham risk score (FRS), Systematic COronary Risk Evaluation (SCORE), pooled cohort equations (PCE), and Reynolds risk score (RRS). We calculated measures of risk discrimination and calibration, and modelled clinical implications of initiating statin therapy in people judged to be at 'high' 10 year CVD risk. Original risk algorithms were recalibrated using the risk factor profile and CVD incidence of target populations. The four algorithms had similar risk discrimination. Before recalibration, FRS, SCORE, and PCE over-predicted CVD risk on average by 10%, 52%, and 41%, respectively, whereas RRS under-predicted by 10%. Original versions of algorithms classified 29-39% of individuals aged ≥40 years as high risk. By contrast, recalibration reduced this proportion to 22-24% for every algorithm. We estimated that to prevent one CVD event, it would be necessary to initiate statin therapy in 44-51 such individuals using original algorithms, in contrast to 37-39 individuals with recalibrated algorithms. CONCLUSION: Before recalibration, the clinical performance of four widely used CVD risk algorithms varied substantially. By contrast, simple recalibration nearly equalized their performance and improved modelled targeting of preventive action to clinical need.

Use of the National Heart, Lung, and Blood Institute Data Repository.

BACKGROUND: Research on data sharing from clinical trials has focused on elucidating perceptions, barriers, and attitudes among trialists and study participants with respect to sharing data. However, little information exists regarding utilization or associated publication of articles once clinical trial data have been widely shared. METHODS: We analyzed administrative records of investigator requests for data access, linked publications, and bibliometrics to describe the use of the National Heart, Lung, and Blood Institute data repository. RESULTS: From January 2000 through May 2016, a total of 370 investigators requested data from 1 or more clinical trials. Requests for trial data have been increasing, with 195 investigators (53%) initiating requests during the last 4.4 years of the study period. The predominant reason for requesting data was post hoc secondary analysis of new questions (72%), followed by analytic or statistical approaches to clinical trials (9%) and meta-analyses or pooled study research (7%). Of 172 requests with online project descriptions, only 2 requests were initiated for reanalysis of primary-outcome findings. Data from 88 of 100 available clinical trials were requested at least once, and the median time from repository availability to first request was 235 days. A total of 277 articles were published on the basis of data from 47 trials. Citation metrics from 224 articles indicated that half of the publications have cumulative citations that rank in the top 34% normalized for subject category and year of publication. CONCLUSIONS: Demand for trial data for secondary analysis has been increasing. Requesting data for the a priori purpose of reanalysis or verification of original findings was rare.

The Productivity of NHLBI-Funded Obesity Research, 1983-2013.

OBJECTIVE: To describe and elucidate the time trends of the academic productivity of NHLBI's obesity-related research funding via bibliometric analysis of 30 years of NHLBI-supported obesity-related publications. METHODS: In total, 3,545 NHLBI-funded obesity-related publications were identified in the Thomson Reuters InCites™ database. Shared references in a community detection algorithm were used to identify publication topics. Characteristics of publications and topical communities were analyzed based on citation count and percentile rank. A percentile rank >90 was considered "highly cited." RESULTS: Obesity-related publications increased more than 10-fold over 30 years, whereas NHLBI-funded publications only increased twofold NHLBI-funded obesity publications were cited a median of 23 times (IQR 8-55, range 0-2,047, mean 52). Thirty percent of these publications were highly cited compared to the expected ten percent. Six topical communities were present in 1983 compared to 16 in 2013. The most highly cited topical areas were sleep (n = 199 publications, 38% highly cited), cardiovascular morbidity and mortality (n = 277, 36%), obesity correlates and consequences (n = 588, 35%), and asthma and inflammation (n = 283, 35%). CONCLUSIONS: NHLBI-funded obesity publications have contributed substantially to the obesity literature, with many highly cited. Publications grew in number and topical diversity over 30 years and grew at a faster rate than total NHLBI publications.

Duration and Degree of Weight Gain and Incident Diabetes in Younger Versus Middle-Aged Black and White Adults: ARIC, CARDIA, and the Framingham Heart Study.

OBJECTIVE: To determine whether duration and degree of weight gain are differentially associated with diabetes risk in younger versus middle-aged black and white adults. RESEARCH DESIGN AND METHODS: We combined data from three cohort studies: Atherosclerosis Risk in Communities (ARIC), Coronary Artery Risk Development in Young Adults (CARDIA), and the Framingham Heart Study. A total of 17,404 participants (56% women; 21% black) were stratified by baseline age (younger: ≥30 and <45 years; middle-aged: ≥45 and <60 years) and examined for incident diabetes (median follow-up 9 years). Duration and degree of gain in BMI were calculated as "BMI-years" above one's baseline BMI. RESULTS: Diabetes incidence per 1,000 person-years in the younger and middle-aged groups was 7.2 (95% CI 5.7, 8.7) and 24.4 (22.0, 26.8) in blacks, respectively, and 3.4 (2.8, 4.0) and 10.5 (9.9, 11.2) in whites, respectively. After adjusting for sex, baseline BMI and other cardiometabolic factors, and age and race interaction terms, gains in BMI-years were associated with higher risk of diabetes in the younger compared with middle-aged groups: hazard ratios for 1-unit increase in log BMI-years in younger versus middle-aged blacks were 1.18 (P = 0.02) and 1.02 (P = 0.39), respectively (P for interaction by age-group = 0.047), and in whites were 1.35 (P < 0.001) and 1.11 (P < 0.001), respectively (P for interaction by age-group = 0.008). CONCLUSIONS: Although middle-aged adults have higher rates of diabetes, younger adults are at greater relative risk of developing diabetes for a given level of duration and degree of weight gain.

Providing Contemporary Access to Historical Biospecimen Collections: Development of the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC).

The National Heart, Lung, and Blood Institute (NHLBI), within the United States' National Institutes of Health (NIH), established a Biorepository in 1976 that initially archived biospecimens from population-based blood product safety surveys. It was later expanded to biospecimens from clinical and epidemiological studies in heart, lung, and blood disorders. The NHLBI also established a Data Repository in 2000 to store and distribute study data from NHLBI-sponsored research. The NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC) was established in 2008 to develop the infrastructure needed to link the contents of these two related NHLBI Repositories, facilitate access to repository resources, and streamline request processes. Three key program subcomponents were developed simultaneously: 1) the linkage of biospecimen electronic inventory records with their clinical or characterization data; 2) the development and implementation of a website with both public-facing information and private processing workspaces; and 3) the development of processes to maximize efficiency via a web-based system while maintaining workflow control, document tracking, and secure processes. The BioLINCC website was launched on October 1, 2009 with eight biospecimen collections and data from 72 research studies. By the end of the fourth online year, 38 biospecimen collections were linked and posted, and data from 108 research studies had been made available for request. The number of registered users by the end of the fourth online year approached 2600, and continues to show a trend towards an increasing rate of new users per year. BioLINCC has fulfilled 381 requests comprising 851 data collections, as well as 600 teaching dataset requests and 75 data renewal agreements. 154 biospecimen requests comprising 147,388 biospecimens were fulfilled or actively in process. We conclude that the BioLINCC program has been successful in its goal to increase the visibility and utilization of NHLBI biospecimen and data repository resources.

Individual education, area income, and mortality and recurrence of myocardial infarction in a Medicare cohort: the National Longitudinal Mortality Study.

BACKGROUND: The Medicare program provides universal access to hospital care for the elderly; however, mortality disparities may still persist in this population. The association of individual education and area income with survival and recurrence post Myocardial Infarction (MI) was assessed in a national sample. METHODS: Individual level education from the National Longitudinal Mortality Study was linked to Medicare and National Death Index records over the period of 1991-2001 to test the association of individual education and zip code tabulation area median income with survival and recurrence post-MI. Survival was partitioned into 3 periods: in-hospital, discharge to 1 year, and 1 year to 5 years and recurrence was partitioned into two periods: 28 day to 1 year, and 1 year to 5 years. RESULTS: First MIs were found in 8,043 women and 7,929 men. In women and men 66-79 years of age, less than a high school education compared with a college degree or more was associated with 1-5 year mortality in both women (HRR 1.61, 95% confidence interval 1.03-2.50) and men (HRR 1.37, 1.06-1.76). Education was also associated with 1-5 year recurrence in men (HRR 1.68, 1.18-2.41, < High School compared with college degree or more), but not women. Across the spectrum of survival and recurrence periods median zip code level income was inconsistently associated with outcomes. Associations were limited to discharge-1 year survival (RR lowest versus highest quintile 1.31, 95% confidence interval 1.03-1.67) and 28 day-1 year recurrence (RR lowest versus highest quintile 1.72, 95% confidence interval 1.14-2.57) in older men. CONCLUSIONS: Despite the Medicare entitlement program, disparities related to individual socioeconomic status remain. Additional research is needed to elucidate the barriers and mechanisms to eliminating health disparities among the elderly.

Differential associations of abdominal visceral, subcutaneous adipose tissue with cardiometabolic risk factors between African and European Americans.

OBJECTIVE: To examine the relative association of abdominal visceral adipose tissue (VAT) with cardiometabolic risk factors between African and European Americans. METHODS: A cross-sectional study of 2,035 African Americans from the Jackson Heart Study (JHS) and 3,170 European Americans from the Framingham Heart Study (FHS) who underwent computed tomography assessment of VAT and subcutaneous adipose tissue (SAT) was conducted. The FHS participants were weighted to match the age distribution of the JHS participants, and the metabolic risk factors were examined by study groups in relation to VAT. RESULTS: JHS participants had higher rates of obesity, hypertension, diabetes, and metabolic syndrome than FHS participants (all P = 0.001). The associations were weaker in JHS women for VAT with blood pressure, triglycerides, HDL-C, and total cholesterol (Pinteraction = 0.03-0.001) than FHS women. In contrast, JHS men had stronger associations for VAT with high triglycerides, low HDL, and metabolic syndrome (all Pinteraction = 0.001) compared to FHS men. Similar associations and gender patterns existed for SAT with most metabolic risk factors. CONCLUSIONS: The relative association between VAT and cardiometabolic risk factors is weaker in JHS women compared to FHS women, whereas stronger associations with triglycerides and HDL were observed in JHS men.

Sharing individual level data from observational studies and clinical trials: a perspective from NHLBI.

There are numerous benefits to the research community from data sharing, and yet the open sharing of participant level data is not without potential pitfalls. In addition to the scientific community, the interests of study participants who volunteered their data must be considered, along with the interests of study investigators who expend a substantial amount of effort into the design, conduct, and analytical plans for the study. The National Heart, Lung, and Blood Institute (NHLBI) has developed a data-sharing protocol focused on balancing the interests of study participants, study investigators, and the research community with independent oversight by the NHLBI IRB. The data repository presently includes individual level data on more than 560,000 participants from 100 Institute-supported clinical trials and observational studies.

Cardiovascular Disease Risk Assessment: Insights from Framingham.

Cardiovascular disease (CVD) is among the leading causes of death and disability worldwide. Since its beginning, the Framingham study has been a leader in identifying CVD risk factors. Clinical trials have demonstrated that when the modifiable risk factors are treated and corrected, the chances of CVD occurring can be reduced. The Framingham study also recognized that CVD risk factors are multifactorial and interact over time to produce CVD. In response, Framingham investigators developed the Framingham Risk Functions (also called Framingham Risk Scores) to evaluate the chance or likelihood of developing CVD in individuals. These functions are multivariate functions (algorithms) that combine the information in CVD risk factors such as sex, age, systolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, smoking behavior, and diabetes status to produce an estimate (or risk) of developing CVD or a component of CVD (such as coronary heart disease, stroke, peripheral vascular disease, or heart failure) over a fixed time, for example, the next 10 years. These estimates of CVD risk are often major inputs in recommending drug treatments such as cholesterol-lowering drugs.

Gene-centric association study of acute chest syndrome and painful crisis in sickle cell disease patients.

Patients with sickle cell disease (SCD) present with a wide range of clinical complications. Understanding this clinical heterogeneity offers the prospects to tailor the right treatments to the right patients and also guide the development of novel therapies. Several environmental (eg, nutrition) and nonenvironmental (eg, fetal hemoglobin levels, α-thalassemia status) factors are known to modify SCD severity. To find new genetic modifiers of SCD severity, we performed a gene-centric association study in 1514 African American participants from the Cooperative Study of Sickle Cell Disease (CSSCD) for acute chest syndrome (ACS) and painful crisis. From the initial results, we selected 36 single nucleotide polymorphism (SNPs) and genotyped them for replication in 387 independent patients from the CSSCD, 318 SCD patients recruited at Georgia Health Sciences University, and 449 patients from the Duke SCD cohort. In the combined analysis, an association between ACS and rs6141803 reached array-wide significance (P = 4.1 × 10(-7)). This SNP is located 8.2 kilobases upstream of COMMD7, a gene highly expressed in the lung that interacts with nuclear factor-κB signaling. Our results provide new leads to gaining a better understanding of clinical variability in SCD, a "simple" monogenic disease.

Blood pressure and the risk of developing diabetes in african americans and whites: ARIC, CARDIA, and the framingham heart study.

OBJECTIVE: We examined the association between high blood pressure and incident type 2 diabetes in African Americans and whites aged 35-54 years at baseline. RESEARCH DESIGN AND METHODS: We combined data from the Atherosclerosis Risk in Communities (ARIC) study, the Coronary Artery Risk Development in Young Adults (CARDIA) study, and the Framingham Heart Study offspring cohort. Overall, 10,893 participants (57% women; 23% African American) were categorized by baseline blood pressure (normal, prehypertension, hypertension) and examined for incident diabetes (median follow-up 8.9 years). RESULTS: Overall, 14.6% of African Americans and 7.9% of whites developed diabetes. Age-adjusted incidence was increasingly higher across increasing blood pressure groups (P values for trend: <0.05 for African American men; <0.001 for other race-sex groups). After adjustment for age, sex, BMI, fasting glucose, HDL cholesterol, and triglycerides, prehypertension or hypertension (compared with normal blood pressure) was associated with greater risks of diabetes in whites (hazard ratio [HR] for prehypertension: 1.32 [95% CI 1.09-1.61]; for hypertension: 1.25 [1.03-1.53]), but not African Americans (HR for prehypertension: 0.86 [0.63-1.17]; for hypertension: 0.92 [0.70-1.21]). HRs for developing diabetes among normotensive, prehypertensive, and hypertensive African Americans versus normotensive whites were: 2.75, 2.28, and 2.36, respectively (P values <0.001). CONCLUSIONS: In African Americans, higher diabetes incidence among hypertensive individuals may be explained by BMI, fasting glucose, triglyceride, and HDL cholesterol. In whites, prehypertension and hypertension are associated with greater risk of diabetes, beyond that explained by other risk factors. African Americans, regardless of blood pressure, have greater risks of developing diabetes than whites.

Relationships of BMI to cardiovascular risk factors differ by ethnicity.

The burden of cardiovascular risk associated with obesity disproportionately affects African Americans and little is known about ethnic/racial differences in the relationship of obesity to cardiometabolic risk. This report assesses whether obesity is similarly associated with cardiometabolic risk factors in African Americans and whites of European ancestry. Cross-sectional observational data from the Jackson Heart Study (JHS) and the Framingham Heart Study (FHS) were compared. This analysis uses participants aged 35-74 years with BMI >18.5 kg/m(2), and free of prevalent cardiovascular disease (CVD), from the initial JHS clinical examination (2000-2004) and the FHS Offspring (1998-2001) and Third Generation (2002-2005) cohorts. Participants were evaluated for the presence of lipid abnormalities, hypertension, and diabetes. Overall, 4,030 JHS (mean age 54 years, 64% women) and 5,245 FHS (mean age 51 years, 54% women) participants were available for analysis. The prevalence of all risk factors except high triglycerides and low high-density lipoprotein (HDL) was substantially higher in JHS (all P < 0.001) and BMI was associated with increasing prevalence of most CVD risk factors within each race. For diabetes mellitus, hypertension, and low HDL, steeper relationships to BMI were observed in FHS than in JHS (P values <0.001-0.016). There were larger proportional increases in risk factor prevalence with increasing BMI in whites than in African Americans. The higher prevalence rates of cardiometabolic risk factors at nearly all levels of BMI in African Americans, however, suggest that additional factors contribute to the burden of CVD risk in African Americans.

Trends in all-cause and cardiovascular disease mortality among women and men with and without diabetes mellitus in the Framingham Heart Study, 1950 to 2005.

BACKGROUND: Despite population declines in all-cause mortality, women with diabetes mellitus may have experienced an increase in mortality rates compared with men. METHODS AND RESULTS: We examined change in all-cause, cardiovascular, and non-cardiovascular disease mortality rates among Framingham Heart Study participants who attended examinations during an "earlier" (1950 to 1975; n=930 deaths) and a "later" (1976 to 2001; n=773 deaths) time period. Diabetes mellitus was defined as casual glucose > or =200 mg/dL, fasting plasma glucose > or =126 mg/dL, or treatment. Among women, the hazard ratios (HRs) for all-cause mortality in the later versus the earlier time period were 0.59 (95% confidence interval, 0.50 to 0.70; P<0.0001) for those without diabetes mellitus and 0.48 (95% confidence interval, 0.32 to 0.71; P=0.002) for those with diabetes mellitus. Similar results were observed in men. Among women and men, the HR of cardiovascular disease mortality declined among those with and without diabetes mellitus. Non-cardiovascular disease mortality declined among women without diabetes mellitus (HR, 0.76; P=0.01), whereas no change was observed among women with diabetes mellitus or among men with or without diabetes mellitus. Individuals with versus those without diabetes mellitus were at increased risk of all-cause mortality in the earlier (HR, 2.44; P<0.0001) and later (HR, 1.95; P<0.0001) time periods. CONCLUSIONS: Reductions in all-cause mortality among women and men with diabetes mellitus have occurred over time. However, mortality rates among individuals with diabetes mellitus remain approximately 2-fold higher compared with individuals without diabetes mellitus.