Individual variations of white matter (WM) tracts are known to be associated with various cognitive and neuropsychiatric traits. Diffusion tensor imaging (DTI) and genome-wide single-nucleotide ...polymorphism (SNP) data from 17,706 UK Biobank participants offer the opportunity to identify novel genetic variants of WM tracts and explore the genetic overlap with other brain-related complex traits. We analyzed the genetic architecture of 110 tract-based DTI parameters, carried out genome-wide association studies (GWAS), and performed post-GWAS analyses, including association lookups, gene-based association analysis, functional gene mapping, and genetic correlation estimation. We found that DTI parameters are substantially heritable for all WM tracts (mean heritability 48.7%). We observed a highly polygenic architecture of genetic influence across the genome (p value = 1.67 × 10
) as well as the enrichment of genetic effects for active SNPs annotated by central nervous system cells (p value = 8.95 × 10
). GWAS identified 213 independent significant SNPs associated with 90 DTI parameters (696 SNP-level and 205 locus-level associations; p value < 4.5 × 10
, adjusted for testing multiple phenotypes). Gene-based association study prioritized 112 significant genes, most of which are novel. More importantly, association lookups found that many of the novel SNPs and genes of DTI parameters have previously been implicated with cognitive and mental health traits. In conclusion, the present study identifies many new genetic variants at SNP, locus and gene levels for integrity of brain WM tracts and provides the overview of pleiotropy with cognitive and mental health traits.
In this article, we develop a Bayesian adaptive design methodology for oncology basket trials with binary endpoints using a Bayesian model averaging framework. Most existing methods seek to borrow ...information based on the degree of homogeneity of estimated response rates across all baskets. In reality, an investigational product may only demonstrate activity for a subset of baskets, and the degree of activity may vary across the subset. A key benefit of our Bayesian model averaging approach is that it explicitly accounts for the possibility that any subset of baskets may have similar activity and that some may not. Our proposed approach performs inference on the basket-specific response rates by averaging over the complete model space for the response rates, which can include thousands of models. We present results that demonstrate that this computationally feasible Bayesian approach performs favorably compared to existing state-of-the-art approaches, even when held to stringent requirements regarding false positive rates.
Summary
Self‐management is integral to effective chronic disease management. Cognitive impairments (CogImp) associated with dementia have not previously been reviewed in diabetes mellitus (DM) ...self‐care. The aims of this study are to know (1) whether CogImp associated with dementia impact self‐care and (2) whether specific CogImp affects key DM self‐care processes. A systematic literature search with a narrative review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelines. This review examined studies published from January, 2000 to February, 2016 describing the relationship between cognition and DM self‐care domains in community dwelling older adults with dementia/CogImp. Eight studies met inclusion criteria. Decrements in all self‐care domains were associated with CogImp. Problem solving was related to reduced disease knowledge (OR 0.87, 95% CI = 0.49‐1.55), resulting in poorer glycemic control. Decision‐making impairments manifested as difficulties in adjusting insulin doses, leading to more hospital admissions. People without CogImp were better able to find/utilize resources by adhering to recommended management (OR 1.03, 95% CI = 1.02‐1.05). A lack of interaction with health care providers was demonstrated through reduced receipt of important routine investigation including eye examinations (ARR = 0.85, 95% CI = 0.85‐0.86), HbA1c testing (ARR = 0.96, 95% CI = 0.96‐0.97), and LDL‐C testing (ARR = 0.91, 95% CI = 0.901‐0.914). People without CogImp had better clinic attendance (OR 2.17, 95% CI = 1.30‐3.70). Action taking deficits were apparent through less self‐testing of blood sugar levels (20.2% vs 24.4%, P = 0.1) resulting in poorer glycemic control, self‐care, and more frequent micro/macrovascular complications. Persons with diabetes and CogImp, particularly in domains of learning, memory and executive function, were significantly impaired in all self‐care tasks.
The cornerstone of effective management in heart failure (HF) is the ability to self-care. Aims include i) To determine factors influencing self-care in HF patients with cognitive impairment (CI) and ...ii) to determine the influence of cognitive domains on self-care in patients with HF and CI.
MEDLINE, CINAHL, EMBASE, EBSCOHost, PsychINFO, ProQuest Research Library, Health Technology Assessment Database, The Cochrane Library, Web of Science and Scopus databases were systematically searched. Original research describing the relationship between cognition and HF self-care in community-dwelling older persons with dementia/CI in English, published in a peer-reviewed journal from 1
January(2000)-22
March(2016) was identified. Study and population characteristics, data sources, self-care processes, methods of cognitive assessment, cognitive domains affected, study outcomes, impact of impairment, and other risk factors of self-care impairment were abstracted by two reviewers.
Of 10,688 studies identified, 14 met the inclusion criteria. Patients with HF and CI ranged from 14 to 73%. Where reported, self-care maintenance adequacy ranged from 50 to 61%; self-care management adequacy ranged from 14 to 36% and self-care confidence adequacy ranged from 0 to 44% on the Self-care of Heart Failure Index (SCHFI). All but one study predicted poor self-care ability according to poor outcome on cognitive testing. Additionally, specific cognitive domain deficits impaired self-care. Subjects with lower cognitive scores were less likely to seek assistance while subjects with depression had poor self-care abilities.
Clinicians must consider the type and severity of impairments in cognitive domains to tailor management. Awareness of depression, self-confidence and support access may modulate self-care ability.
There is an increasing interest in the use of joint models for the analysis of longitudinal and survival data. While random effects models have been extensively studied, these models can be hard to ...implement and the fixed effect regression parameters must be interpreted conditional on the random effects. Copulas provide a useful alternative framework for joint modeling. One advantage of using copulas is that practitioners can directly specify marginal models for the outcomes of interest. We develop a joint model using a Gaussian copula to characterize the association between multivariate longitudinal and survival outcomes. Rather than using an unstructured correlation matrix in the copula model to characterize dependence structure as is common, we propose a novel decomposition that allows practitioners to impose structure (e.g., auto-regressive) which provides efficiency gains in small to moderate sample sizes and reduces computational complexity. We develop a Markov chain Monte Carlo model fitting procedure for estimation. We illustrate the method's value using a simulation study and present a real data analysis of longitudinal quality of life and disease-free survival data from an International Breast Cancer Study Group trial.
We propose a Bayesian generalized low-rank regression model (GLRR) for the analysis of both high-dimensional responses and covariates. This development is motivated by performing searches for ...associations between genetic variants and brain imaging phenotypes. GLRR integrates a low rank matrix to approximate the high-dimensional regression coefficient matrix of GLRR and a dynamic factor model to model the high-dimensional covariance matrix of brain imaging phenotypes. Local hypothesis testing is developed to identify significant covariates on high-dimensional responses. Posterior computation proceeds via an efficient Markov chain Monte Carlo algorithm. A simulation study is performed to evaluate the finite sample performance of GLRR and its comparison with several competing approaches. We apply GLRR to investigate the impact of 1071 SNPs on top 40 genes reported by AlzGene database on the volumes of 93 regions of interest (ROI) obtained from Alzheimer's Disease Neuroimaging Initiative (ADNI). Supplementary materials for this article are available online.
We consider selecting both fixed and random effects in a general class of mixed effects models using maximum penalized likelihood (MPL) estimation along with the smoothly clipped absolute deviation ...(SCAD) and adaptive least absolute shrinkage and selection operator (ALASSO) penalty functions. The MPL estimates are shown to possess consistency and sparsity properties and asymptotic normality. A model selection criterion, called the IC Q statistic, is proposed for selecting the penalty parameters (Ibrahim, Zhu, and Tang, 2008, Journal of the American Statistical Association 103, 1648-1658). The variable selection procedure based on IC Q is shown to consistently select important fixed and random effects. The methodology is very general and can be applied to numerous situations involving random effects, including generalized linear mixed models. Simulation studies and a real data set from a Yale infant growth study are used to illustrate the proposed methodology.
There has been increased interest in the design and analysis of studies consisting of multiple response variables of mixed types. For example, in clinical trials, it is desirable to establish ...efficacy for a treatment effect in primary and secondary outcomes. In this article, we develop Bayesian approaches for hypothesis testing and study planning for data consisting of multiple response variables of mixed types with covariates. We assume that the responses are correlated via a Gaussian copula, and that the model for each response is, marginally, a generalized linear model (GLM). Taking a fully Bayesian approach, the proposed method enables inference based on the joint posterior distribution of the parameters. Under some mild conditions, we show that the joint distribution of the posterior probabilities under any Bayesian analysis converges to a Gaussian copula distribution as the sample size tends to infinity. Using this result, we develop an approach to control the type I error rate under multiple testing. Simulation results indicate that the method is more powerful than conducting marginal regression models and correcting for multiplicity using the Bonferroni‐Holm Method. We also develop a Bayesian approach to sample size determination in the presence of response variables of mixed types, extending the concept of probability of success (POS) to multiple response variables of mixed types.
Objectives
To describe the frequency and nature of deaths from resident‐to‐resident aggression (RRA) in nursing homes in Australia.
Design
National population‐based retrospective cohort study.
...Setting
Accredited nursing homes in Australia.
Participants
Residents whose deaths resulted from RRA and were reported to the coroner between July 1, 2000, and December 31, 2013.
Measurements
Cases were identified using the National Coronial Information System, and data on individual, interpersonal, organizational, and societal factors were collected through review of the paper‐based coroners' files.
Results
This research identified 28 deaths from RRA over a 14‐year study period (0.004 per 100,000 bed days). Most exhibitors of aggression were male (n = 24, 85.7%), and risk of death from RRA was twice as high for male as for female nursing home residents (relative risk (RR) = 2.13, 95% confidence interval (CI) = 0.93–4.80, P = .05). Almost 90% of residents involved in RRA had a diagnosis of dementia, and three‐quarters had a history of behavioral problems, including wandering and aggression. Dyad analysis showed that exhibitors of aggression were often younger and more recently admitted to the nursing home than targets. RRA incidents commonly occurred in communal areas and during the afternoon and involved a “push and fall.” Seven (25%) RRA deaths had a coronial inquest; criminal charges were rarely filed.
Conclusion
This is the first national study in Australia, and the largest internationally, to examine RRA deaths using medicolegal data. This generates hypotheses for future research on the effect of environmental and organizational factors on the frequency and preventability of RRA.
Summary
Joint models for recurrent event and terminating event data are increasingly used for the analysis of clinical trials. However, few methods have been proposed for designing clinical trials ...using these models. In this article, we develop a Bayesian clinical trial design methodology focused on evaluating the effect of an investigational product (IP) on both recurrent event and terminating event processes considered as multiple primary endpoints, using a multifrailty joint model. Dependence between the recurrent and terminating event processes is accounted for using a shared frailty. Inferences for the multiple primary outcomes are based on posterior model probabilities corresponding to mutually exclusive hypotheses regarding the benefit of IP with respect to the recurrent and terminating event processes. We propose an approach for sample size determination to ensure the trial design has a high power and a well-controlled type I error rate, with both operating characteristics defined from a Bayesian perspective. We also consider a generalization of the proposed parametric model that uses a nonparametric mixture of Dirichlet processes to model the frailty distributions and compare its performance to the proposed approach. We demonstrate the methodology by designing a colorectal cancer clinical trial with a goal of demonstrating that the IP causes a favorable effect on at least one of the two outcomes but no harm on either.
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