Abstract Objective To describe the design and ongoing conduct of the Million Veteran Program (MVP), as an observational cohort study and mega-biobank in the Department of Veterans Affairs (VA) health ...care system. Study Design and Setting Data are being collected from participants using questionnaires, the VA electronic health record, and a blood sample for genomic and other testing. Several ongoing projects are linked to MVP, both as peer-reviewed research studies and as activities to help develop an infrastructure for future, broad-based research uses. Results Formal planning for MVP commenced in 2009; the protocol was approved in 2010, and enrollment began in 2011. As of August 3, 2015, and with a steady state of ≈50 recruiting sites nationwide, N = 397,104 veterans have been enrolled. Among N = 199,348 with currently available genotyping data, most participants (as expected) are male (92.0%) between the ages of 50 and 69 years (55.0%). On the basis of self-reported race, white (77.2%) and African American (13.5%) populations are well represented. Conclusions By helping to promote the future integration of genetic testing in health care delivery, including clinical decision making, the MVP is designed to contribute to the development of precision medicine.
Most patients with pancreatic ductal adenocarcinoma (PDAC) are diagnosed with advanced disease and survive less than 12 months. PDAC has been linked with obesity and glucose intolerance, but whether ...changes in circulating metabolites are associated with early cancer progression is unknown. To better understand metabolic derangements associated with early disease, we profiled metabolites in prediagnostic plasma from individuals with pancreatic cancer (cases) and matched controls from four prospective cohort studies. We find that elevated plasma levels of branched-chain amino acids (BCAAs) are associated with a greater than twofold increased risk of future pancreatic cancer diagnosis. This elevated risk was independent of known predisposing factors, with the strongest association observed among subjects with samples collected 2 to 5 years before diagnosis, when occult disease is probably present. We show that plasma BCAAs are also elevated in mice with early-stage pancreatic cancers driven by mutant Kras expression but not in mice with Kras-driven tumors in other tissues, and that breakdown of tissue protein accounts for the increase in plasma BCAAs that accompanies early-stage disease. Together, these findings suggest that increased whole-body protein breakdown is an early event in development of PDAC.
The adipocyte-secreted hormone adiponectin has insulin-sensitizing and anti-inflammatory properties. Although development of pancreatic cancer is associated with states of insulin resistance and ...chronic inflammation, the mechanistic basis of the associations is poorly understood.
To determine whether prediagnostic plasma levels of adiponectin are associated with risk of pancreatic cancer, we conducted a nested case-control study of 468 pancreatic cancer case subjects and 1080 matched control subjects from five prospective US cohorts: Health Professionals Follow-up Study, Nurses' Health Study, Physicians' Health Study, Women's Health Initiative, and Women's Health Study. Control subjects were matched to case subjects by prospective cohort, year of birth, smoking status, fasting status, and month of blood draw. All samples for plasma adiponectin were handled identically in a single batch. Odds ratios were calculated with conditional logistic regression, and linearity of the association between adiponectin and pancreatic cancer was modeled with restricted cubic spline regression. All statistical tests were two-sided.
Median plasma adiponectin was lower in case subjects versus control subjects (6.2 vs 6.8 µg/mL, P = .009). Plasma adiponectin was inversely associated with pancreatic cancer risk, which was consistent across the five prospective cohorts (P (heterogeneity) = .49) and independent of other markers of insulin resistance (eg, diabetes, body mass index, physical activity, plasma C-peptide). Compared with the lowest quintile of adiponectin, individuals in quintiles 2 to 5 had multivariable odds ratios (ORs 95% confidence intervals CIs) of OR = 0.61 (95% CI = 0.43 to 0.86), OR = 0.58 (95% CI = 0.41 to 0.84), OR = 0.59 (95% CI = 0.40 to 0.87), and OR = 0.66 (95% CI = 0.44 to 0.97), respectively (P (trend) = .04). Restricted cubic spline regression confirmed a nonlinear association (P (nonlinearity) < .01). The association was not modified by sex, smoking, body mass index, physical activity, or C-peptide (all P (interaction) > .10).
In this pooled analysis, low prediagnostic levels of circulating adiponectin were associated with an elevated risk of pancreatic cancer.
Although sleep quality and duration have been related to cardiovascular end points, little is known about the association between sleep duration and incident atrial fibrillation (AF). Hence, we ...prospectively examined the association between sleep duration and incident AF in a cohort of 18,755 United States male physicians. Self-reported sleep duration was ascertained during a 2002 annual follow-up questionnaire. Incident AF was ascertained through annual follow-up questionnaires. Cox regression analysis was used to estimate the relative risks of AF. The average age at baseline was 67.7 ± 8.6 years. During a mean follow-up of 6.9 ± 2.1 years, 1,468 cases of AF occurred. Using 7 hours of sleep as the reference group, the multivariate adjusted hazard ratio for AF was 1.06 (95% confidence interval 0.92 to 1.22), 1.0 (reference), and 1.13 (95% confidence interval 1.00 to 1.27) from the lowest to greatest category of sleep duration (p for trend = 0.26), respectively. In a secondary analysis, no evidence was seen of effect modification by adiposity (p for interaction = 0.69); however, prevalent sleep apnea modified the relation of sleep duration with AF (p for interaction = 0.01). From the greatest to the lowest category of sleep duration, the multivariate-adjusted hazard ratio for AF was 2.26 (95% confidence interval 1.26 to 4.05), 1.0 (reference), and 1.34 (95% confidence interval 0.73 to 2.46) for those with prevalent sleep apnea and 1.01 (95% confidence interval 0.87 to 1.16), 1.0 (reference), and 1.12 (95% confidence interval 0.99 to 1.27) for those without sleep apnea, respectively. Our data showed a modestly elevated risk of AF with long sleep duration among United States male physicians. Furthermore, a shorter sleep duration was associated with a greater risk of AF in those with prevalent sleep apnea.
Aims
This study aims to develop the first race‐specific and sex‐specific risk prediction models for heart failure with preserved (HFpEF) and reduced ejection fraction (HFrEF).
Methods and results
We ...created a cohort of 1.8 million individuals who had an outpatient clinic visit between 2002 and 2007 within the Veterans Affairs (VA) Healthcare System and obtained information on HFpEF, HFrEF, and several risk factors from electronic health records (EHR). Variables were selected for the risk prediction models in a ‘derivation cohort’ that consisted of individuals with baseline date in 2002, 2003, or 2004 using a forward stepwise selection based on a change in C‐index threshold. Discrimination and calibration were assessed in the remaining participants (internal ‘validation cohort’). A total of 66 831 individuals developed HFpEF, and 92 233 developed HFrEF (52 679 and 71 463 in the derivation cohort) over a median of 11.1 years of follow‐up. The HFpEF risk prediction model included age, diabetes, BMI, COPD, previous MI, antihypertensive treatment, SBP, smoking status, atrial fibrillation, and estimated glomerular filtration rate (eGFR), while the HFrEF model additionally included previous CAD. For the HFpEF model, C‐indices were 0.74 (SE = 0.002) for white men, 0.76 (0.005) for black men, 0.79 (0.015) for white women, and 0.77 (0.026) for black women, compared with 0.72 (0.002), 0.72 (0.004), 0.77 (0.017), and 0.75 (0.028), respectively, for the HFrEF model. These risk prediction models were generally well calibrated in each race‐specific and sex‐specific stratum of the validation cohort.
Conclusions
Our race‐specific and sex‐specific risk prediction models, which used easily obtainable clinical variables, can be a useful tool to implement preventive strategies or subtype‐specific prevention trials in the nine million users of the VA healthcare system and the general population after external validation.
A recent genome-wide association study (PanScan) identified significant associations at the ABO gene locus with risk of pancreatic cancer, but the influence of specific ABO genotypes remains unknown. ...We determined ABO genotypes (OO, AO, AA, AB, BO, and BB) in 1,534 cases and 1,583 controls from 12 prospective cohorts in PanScan, grouping participants by genotype-derived serologic blood type (O, A, AB, and B). Adjusted odds ratios (ORs) for pancreatic cancer by ABO alleles were calculated using logistic regression. Compared with blood type O, the ORs for pancreatic cancer in subjects with types A, AB, and B were 1.38 95% confidence interval (95% CI), 1.18-1.62, 1.47 (95% CI, 1.07-2.02), and 1.53 (95% CI, 1.21-1.92), respectively. The incidence rates for blood types O, A, AB, and B were 28.9, 39.9, 41.8, and 44.5 cases per 100,000 subjects per year. An increase in risk was noted with the addition of each non-O allele. Compared with OO genotype, subjects with AO and AA genotype had ORs of 1.33 (95% CI, 1.13-1.58) and 1.61 (95% CI, 1.22-2.18), whereas subjects with BO and BB genotypes had ORs of 1.45 (95% CI, 1.14-1.85) and 2.42 (1.28-4.57). The population attributable fraction for non-O blood type was 19.5%. In a joint model with smoking, current smokers with non-O blood type had an adjusted OR of 2.68 (95% CI, 2.03-3.54) compared with nonsmokers of blood type O. We concluded that ABO genotypes were significantly associated with pancreatic cancer risk.
Although vitamin D inhibits pancreatic cancer proliferation in laboratory models, the association of plasma 25-hydroxyvitamin D 25(OH)D with patient survival is largely unexplored.
We analyzed ...survival among 493 patients from five prospective US cohorts who were diagnosed with pancreatic cancer from 1984 to 2008. We estimated hazard ratios (HRs) for death by plasma level of 25(OH)D (insufficient, < 20 ng/mL; relative insufficiency, 20 to < 30 ng/mL; sufficient ≥ 30 ng/mL) by using Cox proportional hazards regression models adjusted for age, cohort, race and ethnicity, smoking, diagnosis year, stage, and blood collection month. We also evaluated 30 tagging single-nucleotide polymorphisms in the vitamin D receptor gene, requiring P < .002 (0.05 divided by 30 genotyped variants) for statistical significance.
Mean prediagnostic plasma level of 25(OH)D was 24.6 ng/mL, and 165 patients (33%) were vitamin D insufficient. Compared with patients with insufficient levels, multivariable-adjusted HRs for death were 0.79 (95% CI, 0.48 to 1.29) for patients with relative insufficiency and 0.66 (95% CI, 0.49 to 0.90) for patients with sufficient levels (P trend = .01). These results were unchanged after further adjustment for body mass index and history of diabetes (P trend = .02). The association was strongest among patients with blood collected within 5 years of diagnosis, with an HR of 0.58 (95% CI, 0.35 to 0.98) comparing patients with sufficient to patients with insufficient 25(OH)D levels. No single-nucleotide polymorphism at the vitamin D receptor gene met our corrected significance threshold of P < .002; rs7299460 was most strongly associated with survival (HR per minor allele, 0.80; 95% CI, 0.68 to 0.95; P = .01).
We observed longer overall survival in patients with pancreatic cancer who had sufficient prediagnostic plasma levels of 25(OH)D.
This study aimed to assess a four-marker protein panel (4MP)’s performance, including the precursor form of surfactant protein B, cancer antigen 125, carcinoembryonic antigen, and cytokeratin-19, for ...predicting lung cancer in a cohort enriched with never- and ever-smokers. Blinded pre-diagnostic plasma samples collected within 2 years prior to a lung cancer diagnosis from 25 cases and 100 sex-, age-, and smoking-matched controls were obtained from the Physicians’ Health Study (PHS). The 4MP yielded AUC performance estimates of 0.76 (95% CI: 0.61–0.92) and 0.69 (95% CI: 0.56–0.82) for predicting lung cancer within one year and within two years of diagnosis, respectively. When stratifying into ever-smokers and never-smokers, the 4MP had respective AUCs of 0.77 (95% CI: 0.63–0.92) and 0.72 (95% CI: 0.17–1.00) for a 1-year risk of lung cancer. The AUCs of the 4MP for predicting metastatic lung cancer within one year and two years of the blood draw were 0.95 (95% CI: 0.87–1.00) and 0.78 (95% CI: 0.62–0.94), respectively. Our findings indicate that a blood-based biomarker panel may be useful in identifying ever- and never-smokers at high risk of a diagnosis of lung cancer within one-to-two years.
Electronic frailty indices based on data from administrative claims and electronic health records can be used to estimate frailty in large populations of older adults with cancer where direct frailty ...measures are lacking. The objective of this study was to use the electronic Veterans Affairs Frailty Index (VA-FI-10)—developed and validated to measure frailty in the national United States (US) VA Healthcare System—to estimate the prevalence and impact of frailty in older US veterans newly treated for multiple myeloma (MM) with contemporary therapies. We designed a retrospective cohort study of 4924 transplant-ineligible veterans aged ≥ 65 years initiating MM therapy within VA from 2004 to 2017. Initial MM therapy was measured using inpatient and outpatient treatment codes from pharmacy data in the VA Corporate Data Warehouse. In total, 3477 veterans (70.6%) were classified as frail (VA-FI-10 > 0.2), with 1510 (30.7%) mildly frail (VA-FI-10 > 0.2–0.3), 1105 (22.4%) moderately frail (VA-FI-10 > 0.3–0.4), and 862 (17.5%) severely frail (VA-FI-10 > 0.4). Survival and time to hospitalization decreased with increasing VA-FI-10 severity (log-rank p-value < 0.001); the VA-FI-10 predicted mortality and hospitalizations independently of age, sociodemographic variables, and measures of disease risk. Varying data sources and assessment periods reclassified frailty severity for a substantial portion of veterans but did not substantially affect VA-FI-10’s association with mortality. Our study supports use of the VA-FI-10 in future research involving older veterans with MM and provides insights into its potential use in identifying frailty in clinical practice.
Previous studies have suggested that vitamin D deficiency might contribute to the pathogenesis of heart failure (HF); however, limited data are available on the association of vitamin D-binding ...protein (VDBP)—a major transport protein for vitamin D—and the development of HF. Thus, we investigated whether plasma VDBP is inversely associated with HF risk. Using a prospective nested case-control design, we selected 464 cases and 464 matched controls from the Physicians' Health Study for the present analyses. VDBP was determined using an enzyme-linked immunoassay. Self-reported HF was obtained through annual follow-up questionnaires and validated in a subsample by a review of the medical records. We used conditional logistic regression analyses to compute the adjusted odds ratios. The mean age was 58.6 years, and the median VDBP was 307.8 μg/ml (interquartile range 265.2 to 354.6). Plasma VDBP was not associated with HF in our study. Across the consecutive quintiles of VDBP, the odds ratio was 1.0 (95% confidence interval CI reference), 1.05 (95% CI 0.66 to 1.65), 1.28 (95% CI 0.80 to 2.06), 1.07 (95% CI 0.65 to 1.75), and 1.28 (95% CI 0.76 to 2.15); p for linear trend = 0.41, after adjustment for matching factors, body mass index, diabetes, atrial fibrillation, hypertension, and high-sensitivity C-reactive protein. In conclusion, our data have shown no significant association between the plasma levels of VDBP and HF risk in apparently healthy male physicians.
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