Integrating additional knowledge into the estimation of graphical models.

Graphical models such as brain connectomes derived from functional magnetic resonance imaging (fMRI) data are considered a prime gateway to understanding network-type processes. We show, however, that standard methods for graphical modeling can fail to provide accurate graph recovery even with optimal tuning and large sample sizes. We attempt to solve this problem by leveraging information that is often readily available in practice but neglected, such as the spatial positions of the measurements. This information is incorporated into the tuning parameter of neighborhood selection, for example, in the form of pairwise distances. Our approach is computationally convenient and efficient, carries a clear Bayesian interpretation, and improves standard methods in terms of statistical stability. Applied to data about Alzheimer's disease, our approach allows us to highlight the central role of lobes in the connectivity structure of the brain and to identify an increased connectivity within the cerebellum for Alzheimer's patients compared to other subjects.

Primary and Repeated Respiratory Viral Infections Among Infants in Rural Nepal.

BACKGROUND: Respiratory viruses cause significant morbidity and death in infants; 99% of such deaths occur in resource-limited settings. Risk factors for initial and repeated respiratory viral infections in young infants in resource-limited settings have not been well described. METHODS: From 2011 to 2014, a birth cohort of infants in rural Nepal was enrolled and followed with weekly household-based active surveillance for respiratory symptoms until 6 months of age. Respiratory illness was defined as having any of the following: fever, cough, wheeze, difficulty breathing, and/or a draining ear. We tested nasal swabs of infants with respiratory illness for multiple respiratory viruses by using a reverse transcription polymerase chain reaction assay. The risk of primary and repeated infections with the same virus was evaluated using Poisson regression. RESULTS: Of 3528 infants, 1726 (49%) had a primary infection, and 419 (12%) had a repeated infection. The incidences of respiratory viral infection in infants were 1816 per 1000 person-years for primary infections and 1204 per 1000 person-years for repeated infection with the same virus. Exposure to other children and male sex were each associated with an increased risk for primary infection (risk ratios, 1.13 [95% confidence interval (CI), 1.06-1.20] and 1.14 [95% CI, 1.02-1.27], respectively), whereas higher maternal education was associated with a decreased risk for both primary and repeated infections (risk ratio, 0.96 [95% CI, 0.95-0.98]). The incidence of subsequent infection did not change when previous infection with the same or another respiratory virus occurred. Illness duration and severity were not significantly different in the infants between the first and second episodes for any respiratory virus tested. CONCLUSIONS: In infants in rural Nepal, repeated respiratory virus infections were frequent, and we found no decrease in illness severity with repeated infections and no evidence of replacement with another virus. Vaccine strategies and public health interventions that provide durable protection in the first 6 months of life could decrease the burden of repeated infections by multiple respiratory viruses, particularly in low-resource countries.

Biomarker-calibrated nutrient intake and healthy diet index associations with mortality risks among older and frail women from the Women's Health Initiative.

Background: Although studies to date have confirmed the association between nutrition and frailty, the impact of dietary intake and dietary patterns on survivorship in those with frailty is yet to be examined in a well-powered cohort with validated frailty status. Moreover, previous studies were limited by measurement error from dietary self-reports.Objective: We derived biomarker-calibrated dietary energy and protein intakes to address dietary self-report error. Using these data, we then evaluated the association of mortality in older women with frailty and dietary intake and healthy diet indexes, such as the alternate Mediterranean Diet (aMED), the Dietary Approaches to Stop Hypertension (DASH) score, and the Dietary Inflammatory Index (DII).Design: The analytic sample included 10,034 women aged 65-84 y with frailty and complete dietary data from the Women's Health Initiative Observational Study. Frailty was assessed with modified Fried's criteria. Dietary data were collected by food-frequency questionnaire.Results: Over a mean follow-up period of 12.4 y, 3259 (31%) deaths occurred. The HRs showed progressively decreased rates of mortality in women with higher calibrated dietary energy intakes (P-trend = 0.003), higher calibrated dietary protein intakes (P-trend = 0.03), higher aMED scores (P-trend = 0.006), and higher DASH scores (P-trend = 0.02). Although the adjusted point estimates of HRs (95% CIs) for frail women scoring in the second, third, and fourth quartiles on DII measures were 1.15 (1.03, 1.27), 1.28 (1.15, 1.42), and 1.24 (1.12, 1.38), respectively, compared with women in the first quartile, no overall effect was observed across quartiles (P-trend = 0.35). Subgroup analyses by chronic morbidity or smoking status or by excluding women with early death did not substantially change these findings.Conclusions: The current study highlights the importance of nutrition in older, frail women. Diet quality and quantity should be considered in managing persons with frailty.

Statistical evaluation of drug efficacy for bridging study in companion diagnostic test trials.

Personalized medicine is an area of growing attention in medical research and practice. A market-ready companion diagnostic test (CDx) is used in personalized medicine for identifying the best treatment for an individual patient. Unfortunately, development of CDx may lag behind the development of the drug, and consequently we use a clinical trial assay (CTA) to enroll patients into the drug pivotal clinical trial instead. Thus, when CDx becomes available, a bridging study will be required to assess the drug efficacy in the CDx intended use (CDx IU) population. Due to missingness of the CDx results that could be associated with randomization, one challenge we face in a bridging study is covariate imbalance between treatment arms for the subpopulation with both positive CDx and CTA. In this paper, we evaluate the performance of two methods in bridging studies under a causal inference framework. Particularly, we aim to use the propensity score method with doubly robust estimation and optimal matching to address the challenge. We extend under a current framework on drug efficacy estimation in the CDx IU population, using data from both the bridging study and the CTA drug pivotal clinical trial. Both approaches are discussed in the context of a randomized bridging study, and a targeted design clinical trial with simulations, followed by analyzing simulated data that mimic a real ongoing clinic trial.

Results From the NACC Uniform Data Set Neuropsychological Battery Crosswalk Study.

INTRODUCTION: Four new nonproprietary tests were recommended for use in the National Alzheimer's Coordinating Center's Uniform Data Set Neuropsychological Battery. These tests are similar to previous tests but also allow for continuity of longitudinal data collection and wide dissemination among research collaborators. METHODS: A Crosswalk Study was conducted in early 2014 to assess the correlation between each set of new and previous tests. Tests with good correlation were equated using equipercentile equating. The resulting conversion tables allow scores on the new tests to be converted to equivalent scores on the previous tests. RESULTS: All pairs of tests had good correlation (ρ=0.68 to 0.78). Learning effects were detected for Logical Memory only. Confidence intervals were narrow at each point estimate, and prediction accuracy was high. DISCUSSION: The recommended new tests are well correlated with the previous tests. The equipercentile equating method produced conversion tables that provide a useful reference for clinicians and researchers.

Multisite assessment of NIA-AA guidelines for the neuropathologic evaluation of Alzheimer's disease.

INTRODUCTION: Neuropathologic assessment is the current "gold standard" for evaluating the Alzheimer's disease (AD), but there is no consensus on the methods used. METHODS: Fifteen unstained slides (8 brain regions) from each of the 14 cases were prepared and distributed to 10 different National Institute on Aging AD Centers for application of usual staining and evaluation following recently revised guidelines for AD neuropathologic change. RESULTS: Current practice used in the AD Centers Program achieved robustly excellent agreement for the severity score for AD neuropathologic change (average weighted κ = .88, 95% confidence interval: 0.77-0.95) and good-to-excellent agreement for the three supporting scores. Some improvement was observed with consensus evaluation but not with central staining of slides. Evaluation of glass slides and digitally prepared whole-slide images was comparable. DISCUSSION: AD neuropathologic evaluation as performed across AD Centers yields data that have high agreement with potential modifications for modest improvements.