Semi-parametric benchmark dose analysis with monotone additive models.

Benchmark dose analysis aims to estimate the level of exposure to a toxin associated with a clinically significant adverse outcome and quantifies uncertainty using the lower limit of a confidence interval for this level. We develop a novel framework for benchmark dose analysis based on monotone additive dose-response models. We first introduce a flexible approach for fitting monotone additive models via penalized B-splines and Laplace-approximate marginal likelihood. A reflective Newton method is then developed that employs de Boor's algorithm for computing splines and their derivatives for efficient estimation of the benchmark dose. Finally, we develop a novel approach for calculating benchmark dose lower limits based on an approximate pivot for the nonlinear equation solved by the estimated benchmark dose. The favorable properties of this approach compared to the Delta method and a parameteric bootstrap are discussed. We apply the new methods to make inferences about the level of prenatal alcohol exposure associated with clinically significant cognitive defects in children using data from six NIH-funded longitudinal cohort studies. Software to reproduce the results in this paper is available online and makes use of the novel semibmd  R package, which implements the methods in this paper.

Genetic admixture predictors of fetal alcohol spectrum disorders (FASD) in a South African population.

Ancestrally admixed populations are underrepresented in genetic studies of complex diseases, which are still dominated by European-descent populations. This is relevant not only from a representation standpoint but also because of admixed populations' unique features, including being enriched for rare variants, for which effect sizes are disproportionately larger than common polymorphisms. Furthermore, results from these populations may be generalizable to other populations. The South African Cape Coloured (SACC) population is genetically admixed and has one of the highest prevalences of fetal alcohol spectrum disorders (FASD) worldwide. We profiled its admixture and examined associations between ancestry profiles and FASD outcomes using two longitudinal birth cohorts (N=308 mothers, 280 children) designed to examine effects of prenatal alcohol exposure on development. Participants were genotyped via MEGAex array to capture common and rare variants. Rare variants were overrepresented in our SACC cohorts, with numerous polymorphisms being monomorphic in other reference populations (e.g., ∼30,000 and âˆ¼ 221,000 variants in gnomAD European and Asian populations, respectively). The cohorts showed global African (51 %; Bantu and San); European (26 %; Northern/Western); South Asian (18 %); and East Asian (5 %; largely Southern regions) ancestries. The cohorts exhibited high rates of homozygosity (6 %), with regions of homozygosity harboring more deleterious variants when lying within African local-ancestry genomic segments. Both maternal and child ancestry profiles were associated with higher FASD risk, and maternal and child ancestry-by-prenatal alcohol exposure interaction effects were seen on child cognition. Our findings indicate that the SACC population may be a valuable asset to identify novel disease-associated genetic loci for FASD and other diseases.

A computationally efficient sequential regression imputation algorithm for multilevel data.

Due to the computational burden, especially in high-dimensional settings, sequential imputation may not be practical. In this paper, we adopt computationally advantageous methods by sampling the missing data from their perspective predictive distributions, which leads to significantly improved computation time in the class of variable-by-variable imputation algorithms. We assess the computational performance in a comprehensive simulation study. We then compare and contrast the performance of our algorithm with commonly used alternatives. The results show that our method has a significant advantage over the commonly used alternatives with respect to computational efficiency and inferential quality. Finally, we demonstrate our methods in a substantive problem aimed at investigating the effects of area-level behavioral, socioeconomic, and demographic characteristics on poor birth outcomes in New York State among singleton births.

Benchmark dose profiles for bivariate exposures.

While benchmark dose (BMD) methodology is well-established for settings with a single exposure, these methods cannot easily handle multidimensional exposures with nonlinear effects. We propose a framework for BMD analysis to characterize the joint effect of a two-dimensional exposure on a continuous outcome using a generalized additive model while adjusting for potential confounders via propensity scores. This leads to a dose-response surface which can be summarized in two dimensions by a contour plot in which combinations of exposures leading to the same expected effect are identified. In our motivating study of prenatal alcohol exposure, cognitive deficits in children are found to be associated with both the frequency of drinking as well as the amount of alcohol consumed on each drinking day during pregnancy. The general methodological framework is useful for a broad range of settings, including combinations of environmental stressors, such as chemical mixtures, and in explorations of the impact of dose rate rather than simply cumulative exposure on adverse outcomes.

Genetic admixture predictors of fetal alcohol spectrum disorders (FASD) in the South African Cape Coloured population.

Ancestrally admixed populations are underrepresented in genetic studies of complex diseases, which are still dominated by European-descent populations. This is relevant not only from a representation standpoint but also because of admixed populations' unique features, including being enriched for rare variants, for which effect sizes are disproportionately larger than common polymorphisms. Furthermore, results from these populations may be generalizable to other populations. The South African Cape Coloured (SACC) population is genetically admixed, with one of the highest prevalences of fetal alcohol spectrum disorders (FASD) worldwide. We profiled its admixture and examined associations between ancestry profiles and FASD outcomes using two longitudinal birth cohorts ( N =308 mothers, 280 children) designed to examine effects of prenatal alcohol exposure on development. Participants were genotyped via MEGA-ex array to capture common and rare variants. Rare variants were overrepresented in our SACC cohorts, with numerous polymorphisms being monomorphic in other reference populations (e.g., ∼30,000 and ∼221,000 variants in gnomAD European and Asian populations, respectively). The cohorts showed global African (51%; Bantu and San); European (26%; Northern/Western); South Asian (18%); and East Asian (5%; largely Southern regions) ancestries. The cohorts exhibited high rates of homozygosity (6%), with regions of homozygosity harboring more deleterious variants when lying within African local-ancestry genomic segments. Both maternal and child ancestry profiles were associated with FASD risk and altered severity of prenatal alcohol exposure-related cognitive deficits in the child. Our findings indicate that the SACC population may be a valuable asset to identify novel disease-associated genetic loci for FASD and other diseases.

Meta-analysis on studies with heterogeneous and partially observed covariates.

Individual participant data meta-analysis is a commonly used alternative to the traditional aggregate data meta-analysis. It is popular because it avoids relying on published results and enables direct adjustment for relevant covariates. However, a practical challenge is that the studies being combined often vary in terms of the potential confounders that were measured. Furthermore, it will inevitably be the case that some individuals have missing values for some of those covariates. In this paper, we demonstrate how these challenges can be resolved using a propensity score approach, combined with multiple imputation, as a strategy to adjust for covariates in the context of individual participant data meta-analysis. To illustrate, we analyze data from the Bill and Melinda Gates Foundation-funded Healthy Birth, Growth, and Development Knowledge Integration project to investigate the relationship between physical growth rate in the first year of life and cognition measured later during childhood. We found that the overall effect of average growth velocity on cognitive outcome is slightly, but significantly, positive with an estimated effect size of 0.36 (95% CI 0.18, 0.55).

A dose-response analysis of the effects of prenatal alcohol exposure on cognitive development.

BACKGROUND: Most studies of the effects of prenatal alcohol exposure (PAE) on cognitive function have assumed that the dose-response curve is linear. However, data from a few animal and human studies suggest that there may be an inflection point in the dose-response curve above which PAE effects are markedly stronger and that there may be differences associated with pattern of exposure, assessed in terms of alcohol dose per drinking occasion and drinking frequency. METHODS: We performed second-order confirmatory factor analysis on data obtained at school age, adolescence, and early adulthood from 2227 participants in six US longitudinal cohorts to derive a composite measure of cognitive function. Regression models were constructed to examine effects of PAE on cognitive function, adjusted for propensity scores. Analyses based on a single predictor (absolute alcohol (AA)/day) were compared with analyses based on two predictors (dose/occasion and drinking frequency), using (1) linear models and (2) nonparametric general additive models (GAM) that allow for both linear and nonlinear effects. RESULTS: The single-predictor GAM model showed virtually no nonlinearity in the effect of AA/day on cognitive function. However, the two-predictor GAM model revealed differential effects of maternal drinking pattern. Among offspring of infrequent drinkers, PAE effects on cognitive function were markedly stronger in those whose mothers drank more than ~3 drinks/occasion, and the effect of dose/occasion was strongest among the very frequent drinkers. Frequency of drinking did not appear to alter the PAE effect on cognitive function among participants born to mothers who limited their drinking to ~1 drink/occasion or less. CONCLUSIONS: These findings suggest that linear models based on total AA/day are appropriate for assessing whether PAE affects a given cognitive outcome. However, examination of alcohol dose/occasion and drinking frequency is needed to fully characterize the impact of different levels of alcohol intake on cognitive impairment.

Bayesian outcome selection modeling.

In psychiatric and social epidemiology studies, it is common to measure multiple different outcomes using a comprehensive battery of tests thought to be related to an underlying construct of interest. In the research that motivates our work, researchers wanted to assess the impact of in utero alcohol exposure on child cognition and neuropsychological development, which are evaluated using a range of different psychometric tests. Statistical analysis of the resulting multiple outcomes data can be challenging, because the outcomes measured on the same individual are not independent. Moreover, it is unclear, a priori, which outcomes are impacted by the exposure under study. While researchers will typically have some hypotheses about which outcomes are important, a framework is needed to help identify outcomes that are sensitive to the exposure and to quantify the associated treatment or exposure effects of interest. We propose such a framework using a modification of stochastic search variable selection, a popular Bayesian variable selection model and use it to quantify an overall effect of the exposure on the affected outcomes. The performance of the method is investigated empirically and an illustration is given through application using data from our motivating study.

Comparison of examination techniques of anterior and posterior compartments of the leg for the diagnosis of deep vein thrombosis: A new examination technique.

OBJECTIVES: Several examination techniques have been described for the diagnosis of leg deep vein thrombosis. These previously described examination techniques aim to detect muscle pain that occurs secondary to increased pressure in the posterior compartment of the leg. However, to the best of our knowledge no studies investigated the frequency of muscle pain on the anterior compartment in patients with leg deep vein thrombosis the objective of this study is to investigate the prevalence of muscle pain in the anterior compartment. METHODS: The patients who were diagnosed with acute deep vein thrombosis were included in this prospective cross-sectional study. Each patient was examined using the techniques that determine the pain on the posterior compartment as well as using the technique we described to detect muscle pain on the anterior compartment. RESULTS: Two hunderd forty three patients were enrolled in the study. Among those, both distal and proximal deep vein thrombosis was present in 128 (52.7%) patients. 75% of them had muscle pain in the anterior compartment. CONCLUSION: The results suggested that examination of muscle pain in anterior compartment of leg in patients with both proximal and distal deep vein thrombosis can be used as an additional physical examination techniques for early diagnosis.

Effects of prenatal alcohol exposure on cognitive and behavioral development: Findings from a hierarchical meta-analysis of data from six prospective longitudinal U.S. cohorts.

BACKGROUND: Cognitive and behavioral sequelae of prenatal alcohol exposure (PAE) continue to be prevalent in the United States and worldwide. Because these sequelae are also common in other neurodevelopmental disorders, researchers have attempted to identify a distinct neurobehavioral profile to facilitate the differential diagnosis of fetal alcohol spectrum disorders (FASD). We used an innovative, individual participant meta-analytic technique to combine data from six large U.S. longitudinal cohorts to provide a more comprehensive and reliable characterization of the neurobehavioral deficits seen in FASD than can be obtained from smaller samples. METHODS: Meta-analyses were performed on data from 2236 participants to examine effects of PAE (measured as oz absolute alcohol/day (AA/day)) on IQ, four domains of cognition function (learning and memory, executive function, reading achievement, and math achievement), sustained attention, and behavior problems, after adjusting for potential confounders using propensity scores. RESULTS: The effect sizes for IQ and the four domains of cognitive function were strikingly similar to one another and did not differ at school age, adolescence, or young adulthood. Effect sizes were smaller in the more middle-class Seattle cohort and larger in the three cohorts that obtained more detailed and comprehensive assessments of AA/day. PAE effect sizes were somewhat weaker for parent- and teacher-reported behavior problems and not significant for sustained attention. In a meta-analysis of five aspects of executive function, the strongest effect was on set-shifting. CONCLUSIONS: The similarity in the effect sizes for the four domains of cognitive function suggests that PAE affects an underlying component or components of cognition involving learning and memory and executive function that are reflected in IQ and academic achievement scores. The weaker effects in the more middle-class cohort may reflect a more cognitively stimulating environment, a different maternal drinking pattern (lower alcohol dose/occasion), and/or better maternal prenatal nutrition. These findings identify two domains of cognition-learning/memory and set-shifting-that are particularly affected by PAE, and one, sustained attention, which is apparently spared.

A Multicomponent Approach to Evaluating a Pre-exposure Prophylaxis (PrEP) Implementation Program in Five Agencies in New York.

Research has shown that pre-exposure prophylaxis (PrEP) is effective for preventing HIV infection. We developed the Targeted PrEP Implementation Program (TPIP), an 18-month project that involved five statewide agencies, to assess the extent to which PrEP could be implemented in "real world" clinical settings. The target population was men who have sex with men at high risk for HIV infection. Data were collected from a variety of sources. Implementing PrEP statewide required facilitating provider capacity, developing resources, and identifying/addressing potential barriers. TPIP focused on three key questions: (a) Can providers identify and retain appropriate candidates for PrEP? (b) Can PrEP participants adhere to daily medication? (c) Can PrEP be delivered as part of a comprehensive/integrated plan? There were 171 participating clients, most of whom successfully incorporated PrEP into their daily routines. After addressing initial barriers, we found that PrEP could be routinely delivered as part of a comprehensive prevention plan.

Proximity to Pediatric Cardiac Surgical Care among Adolescents with Congenital Heart Defects in 11 New York Counties.

BACKGROUND: Many individuals with congenital heart defects (CHDs) discontinue cardiac care in adolescence, putting them at risk of adverse health outcomes. Because geographic barriers may contribute to cessation of care, we sought to characterize geographic access to comprehensive cardiac care among adolescents with CHDs. METHODS: Using a population-based, 11-county surveillance system of CHDs in New York, we characterized proximity to the nearest pediatric cardiac surgical care center among adolescents aged 11 to 19 years with CHDs. Residential addresses were extracted from surveillance records documenting 2008 to 2010 healthcare encounters. Addresses were geocoded using ArcGIS and the New York State Street and Address Maintenance Program, a statewide address point database. One-way drive and public transit time from residence to nearest center were calculated using R packages gmapsdistance and rgeos with the Google Maps Distance Matrix application programming interface. A marginal model was constructed to identify predictors associated with one-way travel time. RESULTS: We identified 2522 adolescents with 3058 corresponding residential addresses and 12 pediatric cardiac surgical care centers. The median drive time from residence to nearest center was 18.3 min, and drive time was 30 min or less for 2475 (80.9%) addresses. Predicted drive time was longest for rural western addresses in high poverty census tracts (68.7 min). Public transit was available for most residences in urban areas but for few in rural areas. CONCLUSION: We identified areas with geographic barriers to surgical care. Future research is needed to determine how these barriers influence continuity of care among adolescents with CHDs. Birth Defects Research 109:1494-1503, 2017.© 2017 Wiley Periodicals, Inc.

Utility of Capture-Recapture Methodology to Estimate Prevalence of Congenital Heart Defects Among Adolescents in 11 New York State Counties: 2008 to 2010.

BACKGROUND: Congenital heart defects (CHDs) are the most common birth defects in the United States, and the population of individuals living with CHDs is growing. Though CHD prevalence in infancy has been well characterized, better prevalence estimates among children and adolescents in the United States are still needed. METHODS: We used capture-recapture methods to estimate CHD prevalence among adolescents residing in 11 New York counties. The three data sources used for analysis included Statewide Planning and Research Cooperative System (SPARCS) hospital inpatient records, SPARCS outpatient records, and medical records provided by seven pediatric congenital cardiac clinics from 2008 to 2010. Bayesian log-linear models were fit using the R package Conting to account for dataset dependencies and heterogeneous catchability. RESULTS: A total of 2537 adolescent CHD cases were captured in our three data sources. Forty-four cases were identified in all data sources, 283 cases were identified in two of three data sources, and 2210 cases were identified in a single data source. The final model yielded an estimated total adolescent CHD population of 3845, indicating that 66% of the cases in the catchment area were identified in the case-identifying data sources. Based on 2010 Census estimates, we estimated adolescent CHD prevalence as 6.4 CHD cases per 1000 adolescents (95% confidence interval: 6.2-6.6). CONCLUSION: We used capture-recapture methodology with a population-based surveillance system in New York to estimate CHD prevalence among adolescents. Future research incorporating additional data sources may improve prevalence estimates in this population. Birth Defects Research 109:1423-1429, 2017.© 2017 Wiley Periodicals, Inc.

Correlates of routine HIV testing practices: a survey of New York State primary care physicians, 2011.

BACKGROUND: The New York State (NYS) HIV Testing Law of 2010 mandates that medical providers offer HIV testing to patients aged between 13 and 64 years during primary care, to increase the number of people aware of their infection status, and to ensure linkage to medical treatment. To assess physician practices related to this legislation, we conducted a study to identify the frequency and correlates of routine HIV testing behavior among primary care physicians approximately 15 months after the new law went into effect. METHODS: During September 2011 to January 2012, we mailed self-administered surveys to a representative sample of NYS primary care physicians drawn from the AMA Masterfile of Physicians. Questions included physician practices, knowledge, attitudes, and beliefs related to routine HIV testing. Bivariate and multivariate analyses with a sample of 973 physicians were conducted to identify the most influential predictors of routine HIV testing behaviors. RESULTS: A minority of physicians reported "always" or "frequently" practicing behaviors consistent with routine HIV testing, with 41.7% [95% confidence interval (CI): 37.4 to 46.2] routinely offering tests to patients aged 13-64 years, 40.5% (95% CI: 36.3 to 44.8) to new patients, and 33.3% (95% CI: 29.4 to 37.6) to patients during routine physicals. Only 61.4% (95% CI: 57.4 to 65.6) said they had heard of the new law. In multivariate analyses, specialty, perceived barriers, familiarity with the law, and interaction terms representing familiarity by region and self-efficacy by region were significant predictors across the 3 scenarios of routine HIV testing behavior. CONCLUSIONS: Additional technical assistance and training is needed for physicians on adopting routine testing behaviors, minimizing barriers and enhancing skills.

Routine HIV testing capacity, practices, and perceptions among school-based health center providers in New York State after enactment of the 2010 amended HIV testing law.

BACKGROUND: The 2010 New York State (NYS) HIV Testing Law requires that primary care providers routinely offer HIV testing to patients aged 13-64 years, regardless of risk, and link individuals with HIV to medical care. School-based health centers (SBHCs) are in a position to offer HIV screening to a significant proportion of youth. One year after the law went into effect, we conducted a study to assess whether NYS SBHCs implemented these provisions. METHODS: Medical providers from 83 NYS SBHCs, serving students age 13 and older, participated in a Web-based survey regarding school-based health center capacity for and implementation of routine HIV testing, linkage to care, attitudes, and barriers. RESULTS: On-site HIV testing was reported to be available at 71% of SBHCs. Linkages to age-appropriate HIV care were reported to be available at 85% of SBHCs. The routine offer of HIV testing for eligible students was reported to be implemented at 55% of SBHCs. Forty-one percent reported that HIV testing was offered to at least half of eligible students during the 2010-2011 school year. New York City and high school providers were more likely to report the routine offer of HIV testing, on-site testing, linkages to care, perceive students as willing to test, indicate fewer barriers, and report having offered testing to a majority of eligible students in the previous year. CONCLUSIONS: Many SBHCs have adopted key provisions of the amended NYS HIV Testing Law. Additional assistance may be needed to achieve full implementation; however, especially among SBHCs serving younger populations and those located outside New York City.