Generalized Linear Models with Covariate Measurement Error and Zero-Inflated Surrogates.

Epidemiological studies often encounter a challenge due to exposure measurement error when estimating an exposure-disease association. A surrogate variable may be available for the true unobserved exposure variable. However, zero-inflated data are encountered frequently in the surrogate variables. For example, many nutrient or physical activity measures may have a zero value (or a low detectable value) among a group of individuals. In this paper, we investigate regression analysis when the observed surrogates may have zero values among some individuals of the whole study cohort. A naive regression calibration without taking into account a probability mass of the surrogate variable at 0 (or a low detectable value) will be biased. We developed a regression calibration estimator which typically can have smaller biases than the naive regression calibration estimator. We propose an expected estimating equation estimator which is consistent under the zero-inflated surrogate regression model. Extensive simulations show that the proposed estimator performs well in terms of bias correction. These methods are applied to a physical activity intervention study.

ADAPTIVE TIME LOCATION SAMPLING FOR COMPASS, A SARS-COV-2 PREVALENCE STUDY IN FIFTEEN DIVERSE COMMUNITIES IN THE UNITED STATES.

The COVPN 5002 (COMPASS) study aimed to estimate the prevalence of SARS-CoV-2 (active SARS-CoV-2 or prior SARS-CoV-2 infection) in children and adults attending public venues in 15 socio-demographically diverse communities in the United States. To protect against potential challenges in implementing traditional sampling strategies, time-location sampling (TLS) using complex sampling involving stratification, clustering of units, and unequal probabilities of selection was used to recruit individuals from neighborhoods in selected communities. The innovative design adapted to constraints such as closure of venues; changing infection hotspots; and uncertain policies. Recruitment of children and the elderly raised additional challenges in sample selection and implementation. To address these challenges, the TLS design adaptively updated both the sampling frame and the selection probabilities over time using information acquired from prior weeks. Although the study itself was specific to COVID-19, the strategies presented in this paper could serve as a case study that can be adapted for performing rigorous population-level inferences in similar settings and could help inform rapid and effective responses to future global public health challenges.

Persistence of oral pre-exposure prophylaxis (PrEP) among adolescent girls and young women initiating PrEP for HIV prevention in Kenya.

The Determined, Resilient, Empowered, AIDS-free, Mentored, and Safe (DREAMS) Initiative aims to reduce HIV infections among adolescent girls and young women (AGYW) in Africa. Oral pre-exposure prophylaxis (PrEP) is offered through DREAMS in Kenya to eligible AGYW in high burden counties including Kisumu and Homa Bay. This study examines PrEP persistence among AGYW in high burden community-based PrEP delivery settings. We evaluated PrEP persistence among AGYW in the DREAMS PrEP program in Kisumu and Homa Bay using survival analysis and programmatic PrEP refill data collected between March through December 2017. Among 1,259 AGYW who initiated PrEP during the study period, the median persistence time in the program was 56 days (95% CI: 49-58 days) and the proportion who persisted 3 months later was 37% (95% CI: 34-40%). Persistence varied by county (p < 0.001), age at PrEP initiation (p = 0.002), marital status (p = 0.008), transactional sex (p = 0.002), gender-based violence (GBV) experience (p = 0.009) and current school attendance (p = 0.001) at DREAMS enrollment. Persistence did not vary with orphan status, food insecurity, condom use, age at first sexual encounter or engagement in age-disparate sex at DREAMS enrollment. Targeted strategies are needed to improve AGYW retention in the PrEP program.

Eating behaviors and weight loss outcomes in a 12-month randomized trial of diet and/or exercise intervention in postmenopausal women.

BACKGROUND: Certain eating behaviors are common among women with obesity. Whether these behaviors influence outcomes in weight loss programs, and whether such programs affect eating behaviors, is unclear. METHODS: Our aim was to examine the effect of baseline eating behaviors on intervention adherence and weight among postmenopausal women with overweight or obesity, and to assess intervention effects on eating behaviors. Four hundred and 39 women (BMI ≥25 kg/m2) were randomized to 12 months of: i) dietary weight loss with a 10% weight loss goal ('diet'; n = 118); ii) moderate-to-vigorous intensity aerobic exercise for 225 mins/week ('exercise'; n = 117); iii) combined dietary weight loss and exercise ('diet + exercise'; n = 117); or iv) no-lifestyle change control (n = 87). At baseline and 12 months, restrained eating, uncontrolled eating, emotional eating and binge eating were measured by questionnaire; weight and body composition were assessed. The mean change in eating behavior scores and weight between baseline and 12 months in the diet, exercise, and diet + exercise arms were each compared to controls using the generalized estimating equation (GEE) modification of linear regression adjusted for age, baseline BMI, and race/ethnicity. RESULTS: Baseline restrained eating was positively associated with change in total calories and calories from fat during the dietary intervention but not with other measures of adherence. Higher baseline restrained eating was associated with greater 12-month reductions in weight, waist circumference, body fat and lean mass. Women randomized to dietary intervention had significant reductions in binge eating (- 23.7%, p = 0.005 vs. control), uncontrolled eating (- 24.3%, p < 0.001 vs. control), and emotional eating (- 31.7%, p < 0.001 vs. control) scores, and a significant increase in restrained eating (+ 60.6%, p < 0.001 vs. control); women randomized to diet + exercise reported less uncontrolled eating (- 26.0%, p < 0.001 vs. control) and emotional eating (- 22.0%, p = 0.004 vs. control), and increased restrained eating (+ 41.4%, p < 0.001 vs. control). Women randomized to exercise alone had no significant change in eating behavior scores compared to controls. CONCLUSIONS: A dietary weight loss intervention helped women modify eating behaviors. Future research should investigate optimal behavioral weight loss interventions for women with both disordered eating and obesity. TRIAL REGISTRATION: NCT00470119 (https://clinicaltrials.gov). Retrospectively registered May 7, 2007.

Nested case-control study of telomere length and lung cancer risk among heavy smokers in the ß-Carotene and Retinol Efficacy Trial.

BACKGROUND: Telomeres protect cells from genomic instability. We examined telomere length and lung cancer risk prospectively in heavy smokers. METHODS: In a nested case-control study with 709 cases and 1313 controls, conditional logistic regression was used to evaluate associations between telomere length (global, chromosome 5p, and 13q) and lung cancer risk by histotype, controlling for detailed smoking history. RESULTS: Risks of overall lung cancer and adenocarcinoma were suggestively elevated among individuals with telomere length in the longest tertile. No clear patterns were observed for other histotypes, or for chromosome 5p or 13q telomere length. Associations with adenocarcinoma were strongest among (OR, 95% CI for longest versus shortest tertile): former smokers (2.26, 1.03-4.96), individuals <65 years (2.22, 1.13-4.35), and women (2.21, 0.99-4.93). CONCLUSIONS: Our large study of heavy smokers adds additional evidence that long telomere length prior to diagnosis is associated with risk of lung adenocarcinoma, but not other histotypes.

Repletion of vitamin D associated with deterioration of sleep quality among postmenopausal women.

Reduced health-related quality of life (HRQOL), depressive symptoms and poor sleep quality are important health issues among postmenopausal women and may be associated with low vitamin D status. Overweight postmenopausal women, with serum 25-hydroxyvitamin D [25(OH)D] 10-32ng/m, were recruited in Seattle, WA (2010-2012) and randomly assigned to 12months of weight loss +2000IU oral vitamin D3/day or weight loss+daily placebo. The weight-loss program included a reduced-calorie diet and 225min/week of moderate-to-vigorous aerobic activity. Eight subscales of HRQOL were assessed by the MOS 36-Item Short-Form Health Survey. Depressive symptoms were assessed using the Brief Symptom Inventory-18, and sleep quality was assessed using the Pittsburg Sleep Quality Index (PSQI). Mean 12-month changes in HRQOL, depressive symptoms and sleep quality were compared between groups (intent-to-treat) using generalized estimating equations. Compared to placebo, women receiving vitamin D did not experience any significant change in depressive symptoms (p=0.78), HRQOL subscales (all p>0.05), or overall sleep quality (p=0.21). However, a greater magnitude of change in serum 25(OH)D was associated with an increased need to take medications to sleep (ptrend=0.01) and overall worse sleep quality (ptrend<0.01). Women who became vitamin D replete (≥32ng/mL) also showed a deterioration in total PSQI sleep quality score compared to women who remained <32ng/mL despite supplementation, even after adjusting for relevant covariates (Non-Replete: -5.7% vs. Replete: +6.2%, p<0.01). Vitamin D supplementation of 2000IU/d may result in overall worse sleep quality for postmenopausal women with low circulating vitamin D undergoing weight loss.

Estimation in closed capture-recapture models when covariates are missing at random.

Individual covariates are commonly used in capture-recapture models as they can provide important information for population size estimation. However, in practice, one or more covariates may be missing at random for some individuals, which can lead to unreliable inference if records with missing data are treated as missing completely at random. We show that, in general, such a naive complete-case analysis in closed capture-recapture models with some covariates missing at random underestimates the population size. We develop methods for estimating regression parameters and population size using regression calibration, inverse probability weighting, and multiple imputation without any distributional assumptions about the covariates. We show that the inverse probability weighting and multiple imputation approaches are asymptotically equivalent. We present a simulation study to investigate the effects of missing covariates and to evaluate the performance of the proposed methods. We also illustrate an analysis using data on the bird species yellow-bellied prinia collected in Hong Kong.

Effects of vitamin D supplementation during weight loss on sex hormones in postmenopausal women.

OBJECTIVE: The aim of the study was to compare the effects of vitamin D3 supplementation versus placebo on serum sex hormones in postmenopausal women completing a 12-month diet + exercise weight loss program. METHODS: Two hundred eighteen overweight or obese women (50-75 y) with serum 25-hydroxyvitamin D at least 10 to less than 32 ng/mL ("insufficient") were randomized to either weight loss + 2,000 IU/day oral vitamin D3, or to weight loss + daily placebo. Serum sex hormone-binding globulin, estrone, total, free, and bioavailable estradiol, and testosterone were measured by radioimmunoassay before randomization and at 12 months. Mean changes were compared between groups (intent-to-treat) using generalized estimating equations. RESULTS: The 12-month changes in sex hormone-binding globulin, estrone, total, free, and bioavailable estradiol, and testosterone did not differ between groups (all P > 0.05). However, a greater increase in serum 25-hydroxyvitamin D was associated with a greater increase in sex hormone-binding globulin (Ptrend = 0.01), and larger decreases in free and bioavailable estradiol (Ptrend = 0.04, Ptrend = 0.03, respectively). In post-hoc analyses, we compared women randomized to vitamin D whose serum 25-hydroxyvitamin D remained insufficient (n = 38), to women who became replete (25-hydroxyvitamin D ≥32 ng/mL; n = 53). Replete women showed greater reductions in bioavailable estradiol (-1.8 vs -0.7 pg/mL), free testosterone (-0.8 vs -0.3 pg/mL), and bioavailable testosterone (-1.8 vs -0.6 ng/dL), and a greater increase in sex hormone-binding globulin (10.6 vs 4.7 nmol/L) (all P < 0.05), even after adjusting for differences in total 12-month weight loss. CONCLUSIONS: Overall, 12-month changes in sex hormone did not differ between groups. However, vitamin D repletion was associated with greater reductions in sex hormones during weight loss, with a possible dose-dependent effect. Future studies should test higher doses and target circulating 25-hydroxyvitamin D levels when measuring such effects.

A newly identified susceptibility locus near FOXP1 modifies the association of gastroesophageal reflux with Barrett's esophagus.

BACKGROUND: Important risk factors for esophageal adenocarcinoma and its precursor, Barrett's esophagus, include gastroesophageal reflux disease, obesity, and cigarette smoking. Recently, genome-wide association studies have identified seven germline single-nucleotide polymorphisms (SNP) that are associated with risk of Barrett's esophagus and esophageal adenocarcinoma. Whether these genetic susceptibility loci modify previously identified exposure-disease associations is unclear. METHODS: We analyzed exposure and genotype data from the BEACON Consortium discovery phase GWAS, which included 1,516 esophageal adenocarcinoma case patients, 2,416 Barrett's esophagus case patients, and 2,187 control participants. We examined the seven newly identified susceptibility SNPs for interactions with body mass index, smoking status, and report of weekly heartburn or reflux. Logistic regression models were used to estimate ORs for these risk factors stratified by SNP genotype, separately for Barrett's esophagus and esophageal adenocarcinoma. RESULTS: The odds ratio for Barrett's esophagus associated with at least weekly heartburn or reflux varied significantly with the presence of at least one minor allele of rs2687201 (nominal P = 0.0005, FDR = 0.042). ORs (95% CIs) for weekly heartburn or reflux among participants with 0, 1, or 2 minor alleles of rs2687201 were 6.17 (4.91-7.56), 3.56 (2.85-4.44), and 3.97 (2.47-6.37), respectively. No statistically significant interactions were observed for smoking status and body mass index. CONCLUSION: Reflux symptoms are more strongly associated with Barrett's esophagus risk among persons homozygous for the major allele of rs2687201, which lies approximately 75 kb downstream of the transcription factor gene FOXP1. IMPACT: The novel gene-exposure interaction discovered in this study provides new insights into the etiology of esophageal adenocarcinoma.

Effect of Vitamin D3 Supplementation in Combination with Weight Loss on Inflammatory Biomarkers in Postmenopausal Women: A Randomized Controlled Trial.

Obesity and vitamin D deficiency are associated with risk for several cancers, possibly through inflammation and adipokine-related pathways. Two hundred and eighteen postmenopausal women with BMI > 25 kg/m(2) and low serum 25-hydroxyvitamin D (25(OH)D; ≥10-<32 ng/mL), were randomized to 12 months of either (i) weight-loss intervention + 2000 IU/day oral vitamin D3 or (ii) weight-loss intervention + daily placebo. Serum adiponectin, leptin, TNFα, IL6, IL1ß, IL8, and IL10, were measured by immunoassay, and a composite inflammatory biomarker score calculated. Using generalized estimating equations, mean changes in outcomes were compared between arms (intent-to-treat), adjusted for possible confounders. Analyses were also stratified by weight-loss (gained/no weight-loss; <5%; 5% to 10%; ≥10%). At 12 months, there were no significant differences in analyte changes between arms. In stratified analyses, participants randomized to vitamin D3 who lost 5% to 10% of baseline weight, versus participants who gained weight/had no weight-loss, had significantly greater decreases in levels of IL6 compared with those randomized to placebo: absolute change -0.75 pg/mL (-17.2%), placebo versus -1.77 pg/mL (-37.3%), vitamin D, P = 0.004. Similar but attenuated results were observed for participants who lost ≥10% of baseline weight: -0.41 pg/mL (-13.6%), placebo versus -0.67 pg/mL (-17.3%), vitamin D, P = 0.02. Effects of vitamin D3 supplementation on levels of IL1ß were inconsistent when stratified by weight loss. There were no intervention effects on IL10, TNFα, IL8, the composite score, adiponectin, or leptin, when stratified by weight-loss. In conclusion, vitamin D3 supplementation in combination with weight-loss of at least 5% of baseline weight was associated with significant reductions in levels of IL6.

Esophageal Adenocarcinoma and Its Rare Association with Barrett's Esophagus in Henan, China.

Incidence of esophageal adenocarcinoma (EAC) has increased sharply in Western Europe and United States over the past three decades. Nearly all cases of EAC in the west are thought to be associated with Barrett's esophagus (BE) at the time of diagnosis. Regions in the Henan province of China have one of world's highest incidences of esophageal cancer, yet recent temporal trends in the relative rates of EAC with respect to esophageal squamous-cell carcinoma (ESCC), as well as its association with Barrett's esophagus (BE), have not been reported. In this report, we present large-scale longitudinal clinical and histological data on 5401 esophageal cancers (EC) patients diagnosed during the recent 10-year period (2002-2011) at Henan Cancer Hospital, China. All 217 esophageal adenocarcinoma (EAC) patients from these 5401 EC patients were examined to better understand the relationship between Barrett's esophagus (BE) and EAC. We found that EAC was relatively rare and accounted for approximately 5% of all esophageal cancers each year during 2002-2011. There is no evidence of significant temporal trends in the rate of EAC relative to ESCC. Only 10 out of 217 (4.6%) EAC cases were detected to have any evidence of Barrett's esophagus. This result raises the possibility of a different etiological basis for EAC in China motivating more detailed epidemiological, clinical and molecular characterization of EAC in China in order to better understand the neoplastic development of EAC.

Time to screening in the systems of support to increase colorectal cancer screening trial.

Understanding how interventions affect time to completion of colorectal cancer screening might assist in planning and delivering population-based screening interventions. The Systems of Support to Increase Colorectal Cancer Screening (SOS) study was conducted between 2008 and 2011 at 21 primary care medical centers in Western Washington. Participants in the study, ages 50 to 73 years, were eligible if they were enrolled in Group Health (Seattle, WA) and were due for colorectal cancer screening. Of note, 4,675 recruited participants were randomized to usual care or one of three interventions with incremental levels of systems of support for completion of colorectal cancer screening. We conducted time to screening analyses of the SOS data in years 1 and 2. We investigated whether these effects were time-varying. For year 1, the intervention effects on the time to completion of colorectal cancer screening were the strongest during the first two post-randomization months and then decreased, with no significant effect after the fifth month. For year 2, the intervention effects on the time to colorectal cancer screening increased from the first to the third month and then decreased, with no significant effect after the fifth month. Hence, each of the interventions to increase colorectal cancer screening had its greatest effect within the first 3 months after being offered to participants. Future studies should test whether booster interventions offered later could increase screening rate among those who remain unscreened. Additional research is needed to develop intervention strategies for colorectal cancer screening that focus on sustained behavior over time.

Immunoglobulin genes and the acquisition of HIV infection in a randomized trial of recombinant adenovirus HIV vaccine.

Our knowledge of the host genetic factors that contribute to the acquisition of HIV infection is limited. To identify the host genetic correlates of HIV1 acquisition, we genotyped 777 participants of a randomized trial of recombinant adenovirus HIV1 vaccine for Fcγ receptor IIa (FcγRIIa), FcγRIIIa, and several GM and KM alleles-genetic markers of immunoglobulin γ and κ chains, respectively. None of the genotypes by itself was significantly associated with the acquisition of HIV1 infection. However, particular combinations of GM and KM as well as those of GM and FcγRIIIa loci were significantly associated with the acquisition of HIV1 infection epistatically: KM1/3-GM3/17 (interaction p=0.0246; FDR=0.2952), KM1/3-GM5/21 (interaction p=0.0016; FDR=0.0960), and GM23+/-FcγRIIIa (interaction p=0.0060; FDR=0.1200). These results suggest the involvement of GM, KM, and FcγRIIIa loci in the acquisition of HIV infection. Additional studies are warranted.

Approximate nonparametric corrected-score method for joint modeling of survival and longitudinal data measured with error.

We consider the problem of jointly modeling survival time and longitudinal data subject to measurement error. The survival times are modeled through the proportional hazards model and a random effects model is assumed for the longitudinal covariate process. Under this framework, we propose an approximate nonparametric corrected-score estimator for the parameter, which describes the association between the time-to-event and the longitudinal covariate. The term nonparametric refers to the fact that assumptions regarding the distribution of the random effects and that of the measurement error are unnecessary. The finite sample size performance of the approximate nonparametric corrected-score estimator is examined through simulation studies and its asymptotic properties are also developed. Furthermore, the proposed estimator and some existing estimators are applied to real data from an AIDS clinical trial.