We perform Bayesian inference on historical and late Holocene (last 2000 years) rates of sea-level change. The input data to our model are tide-gauge measurements and proxy reconstructions from cores of coastal sediment. These data are complicated by multiple sources of uncertainty, some of which arise as part of the data collection exercise. Notably, the proxy reconstructions include temporal uncertainty from dating of the sediment core using techniques such as radiocarbon. The model we propose places a Gaussian process prior on the rate of sea-level change, which is then integrated and set in an errors-in-variables framework to take account of age uncertainty. The resulting model captures the continuous and dynamic evolution of sea-level change with full consideration of all sources of uncertainty. We demonstrate the performance of our model using two real (and previously published) example data sets. The global tide-gauge data set indicates that sea-level rise increased from a rate with a posterior mean of 1.13 mm/yr in 1880 AD (0.89 to 1.28 mm/yr 95% credible interval for the posterior mean) to a posterior mean rate of 1.92 mm/yr in 2009 AD (1.84 to 2.03 mm/yr 95% credible interval for the posterior mean). The proxy reconstruction from North Carolina (USA) after correction for land-level change shows the 2000 AD rate of rise to have a posterior mean of 2.44 mm/yr (1.91 to 3.01 mm/yr 95% credible interval). This is unprecedented in at least the last 2000 years.

Surveys often ask respondents to report nonnegative counts, but respondents may misremember or round to a nearby multiple of 5 or 10. This phenomenon is called heaping, and the error inherent in heaped self-reported numbers can bias estimation. Heaped data may be collected cross-sectionally or longitudinally and there may be covariates that complicate the inferential task. Heaping is a well-known issue in many survey settings, and inference for heaped data is an important statistical problem. We propose a novel reporting distribution whose underlying parameters are readily interpretable as rates of misremembering and rounding. The process accommodates a variety of heaping grids and allows for quasi-heaping to values nearly but not equal to heaping multiples. We present a Bayesian hierarchical model for longitudinal samples with covariates to infer both the unobserved true distribution of counts and the parameters that control the heaping process. Finally, we apply our methods to longitudinal self-reported counts of sex partners in a study of high-risk behavior in HIV-positive youth.

Growth charts are widely used in pediatric care for assessing childhood body size measurements (e.g., height or weight). The existing growth charts screen one body size at a single given age. However, when a child has multiple measures over time and exhibits a growth path, how to assess those measures jointly in a rigorous and quantitative way remains largely undeveloped in the literature. In this paper, we develop a new method to construct growth charts for growth paths. A new estimation algorithm using alternating regressions is developed to obtain principal component representations of growth paths (sparse functional data). The new algorithm does not rely on strong distribution assumptions and is computationally robust and easily incorporates subject level covariates, such as parental information. Simulation studies are conducted to investigate the performance of our proposed method, including comparisons to existing methods. When the proposed method is applied to monitor the puberty growth among a group of Finnish teens, it yields interesting insights.

We develop a feature allocation model for inference on genetic tumor variation using next-generation sequencing data. Specifically, we record single nucleotide variants (SNVs) based on short reads mapped to human reference genome and characterize tumor heterogeneity by latent haplotypes defined as a scaffold of SNVs on the same homologous genome. For multiple samples from a single tumor, assuming that each sample is composed of some sample-specific proportions of these haplotypes, we then fit the observed variant allele fractions of SNVs for each sample and estimate the proportions of haplotypes. Varying proportions of haplotypes across samples is evidence of tumor heterogeneity since it implies varying composition of cell subpopulations. Taking a Bayesian perspective, we proceed with a prior probability model for all relevant unknown quantities, including, in particular, a prior probability model on the binary indicators that characterize the latent haplotypes. Such prior models are known as feature allocation models. Specifically, we define a simplified version of the Indian buffet process, one of the most traditional feature allocation models. The proposed model allows overlapping clustering of SNVs in defining latent haplotypes, which reflects the evolutionary process of subclonal expansion in tumor samples.

Although genome-wide association studies (GWAS) have proven powerful for comprehending the genetic architecture of complex traits, they are challenged by a high dimension of single-nucleotide polymorphisms (SNPs) as predictors, the presence of complex environmental factors, and longitudinal or functional natures of many complex traits or diseases. To address these challenges, we propose a high-dimensional varying-coefficient model for incorporating functional aspects of phenotypic traits into GWAS to formulate a so-called functional GWAS or fGWAS. The Bayesian group lasso and the associated MCMC algorithms are developed to identify significant SNPs and estimate how they affect longitudinal traits through time-varying genetic actions. The model is generalized to analyze the genetic control of complex traits using subject-specific sparse longitudinal data. The statistical properties of the new model are investigated through simulation studies. We use the new model to analyze a real GWAS data set from the Framingham Heart Study, leading to the identification of several significant SNPs associated with age-specific changes of body mass index. The fGWAS model, equipped with the Bayesian group lasso, will provide a useful tool for genetic and developmental analysis of complex traits or diseases.

Understanding how genetic variants influence cellular-level processes is an important step toward understanding how they influence important organismal-level traits, or “phenotypes,” including human disease susceptibility. To this end, scientists are undertaking large-scale genetic association studies that aim to identify genetic variants associated with molecular and cellular phenotypes, such as gene expression, transcription factor binding, or chromatin accessibility. These studies use high-throughput sequencing assays (e.g., RNA-seq, ChIP-seq, DNase-seq) to obtain high-resolution data on how the traits vary along the genome in each sample. However, typical association analyses fail to exploit these high-resolution measurements, instead aggregating the data at coarser resolutions, such as genes, or windows of fixed length. Here we develop and apply statistical methods that better exploit the high-resolution data. The key idea is to treat the sequence data as measuring an underlying “function” that varies along the genome, and then, building on wavelet-based methods for functional data analysis, test for association between genetic variants and the underlying function. Applying these methods to identify genetic variants associated with chromatin accessibility (dsQTLs), we find that they identify substantially more associations than a simpler window-based analysis, and in total we identify 772 novel dsQTLs not identified by the original analysis.

Multi-subject functional magnetic resonance imaging (fMRI) data has been increasingly used to study the population-wide relationship between human brain activity and individual biological or behavioral traits. A common method is to regress the scalar individual response on imaging predictors, known as a scalar-on-image (SI) regression. Analysis and computation of such massive and noisy data with complex spatio-temporal correlation structure is challenging. In this article, motivated by a psychological study on human affective feelings using fMRI, we propose a joint Ising and Dirichlet Process (Ising-DP) prior within the framework of Bayesian stochastic search variable selection for selecting brain voxels in high-dimensional SI regressions. The Ising component of the prior makes use of the spatial information between voxels, and the DP component groups the coefficients of the large number of voxels to a small set of values and thus greatly reduces the posterior computational burden. To address the phase transition phenomenon of the Ising prior, we propose a new analytic approach to derive bounds for the hyperparameters, illustrated on 2- and 3-dimensional lattices. The proposed method is compared with several alternative methods via simulations, and is applied to the fMRI data collected from the KLIFF hand-holding experiment.

The onset of several silent, chronic diseases such as diabetes can be detected only through diagnostic tests. Due to cost considerations, self-reported outcomes are routinely collected in lieu of expensive diagnostic tests in large-scale prospective investigations such as the Women’s Health Initiative. However, self-reported outcomes are subject to imperfect sensitivity and specificity. Using a semiparametric likelihood-based approach, we present time to event models to estimate the association of one or more covariates with a error-prone, self-reported outcome. We present simulation studies to assess the effect of error in self-reported outcomes with regard to bias in the estimation of the regression parameter of interest. We apply the proposed methods to prospective data from 152,830 women enrolled in the Women’s Health Initiative to evaluate the effect of statin use with the risk of incident diabetes mellitus among postmenopausal women. The current analysis is based on follow-up through 2010, with a median duration of follow-up of 12.1 years. The methods proposed in this paper are readily implemented using our freely available R software package icensmis, which is available at the Comprehensive R Archive Network (CRAN) website.

Substudies of the Childhood Asthma Management Program [ Control. Clin. Trials 20 (1999) 91–120; N. Engl. J. Med. 343 (2000) 1054–1063] seek to identify patient characteristics associated with asthma symptoms and lung function. To determine if genetic measures are associated with trajectories of lung function as measured by forced vital capacity (FVC), children in the primary cohort study retrospectively had candidate loci evaluated. Given participant burden and constraints on financial resources, it is often desirable to target a subsample for ascertainment of costly measures. Methods that can leverage the longitudinal outcome on the full cohort to selectively measure informative individuals have been promising, but have been restricted in their use to analysis of the targeted subsample. In this paper we detail two multiple imputation analysis strategies that exploit outcome and partially observed covariate data on the nonsampled subjects, and we characterize alternative design and analysis combinations that could be used for future studies of pulmonary function and other outcomes. Candidate predictor (e.g., IL10 cytokine polymorphisms) associations obtained from targeted sampling designs can be estimated with very high efficiency compared to standard designs. Further, even though multiple imputation can dramatically improve estimation efficiency for covariates available on all subjects (e.g., gender and baseline age), relatively modest efficiency gains were observed in parameters associated with predictors that are exclusive to the targeted sample. Our results suggest that future studies of longitudinal trajectories can be efficiently conducted by use of outcome-dependent designs and associated full cohort analysis.

This paper introduces diagnostic tests for the nature of lack of fit in ordinary differential equation models (ODEs) proposed for data. We present a hierarchy of three possible sources of lack of fit: unaccounted-for stochastic variation, misspecification of functional forms in rate equations, and omission of dynamic variables in the description of the system. We represent lack of fit by allowing a parameter vector to vary over time, and propose generic testing procedures that do not rely on specific alternative models. Instead, different sources for lack of fit are characterized in terms of nonparametric relationships among latent variables. The tests are carried out through a combination of residual bootstrap and permutation methods. We demonstrate the effectiveness of these tests on simulated data and on real data from laboratory ecological experiments and electro-cardiogram data.

We propose a novel approach for modeling multivariate longitudinal data in the presence of unobserved heterogeneity for the analysis of the Health and Retirement Study (HRS) data. Our proposal can be cast within the framework of linear mixed models with discrete individual random intercepts; however, differently from the standard formulation, the proposed Covariance Pattern Mixture Model (CPMM) does not require the usual local independence assumption. The model is thus able to simultaneously model the heterogeneity, the association among the responses and the temporal dependence structure.

We focus on the investigation of temporal patterns related to the cognitive functioning in retired American respondents. In particular, we aim to understand whether it can be affected by some individual socio-economical characteristics and whether it is possible to identify some homogenous groups of respondents that share a similar cognitive profile. An accurate description of the detected groups allows government policy interventions to be opportunely addressed.

Results identify three homogenous clusters of individuals with specific cognitive functioning, consistent with the class conditional distribution of the covariates. The flexibility of CPMM allows for a different contribution of each regressor on the responses according to group membership. In so doing, the identified groups receive a global and accurate phenomenological characterization.

Consider a classification problem where we do not have access to labels for individual training examples, but only have average labels over subpopulations. We give practical examples of this setup and show how such a classification task can usefully be analyzed as a weakly supervised clustering problem. We propose three approaches to solving the weakly supervised clustering problem, including a latent variables model that performs well in our experiments. We illustrate our methods on an analysis of aggregated elections data and an industry data set that was the original motivation for this research.

We consider the problem of jointly estimating a collection of graphical models for discrete data, corresponding to several categories that share some common structure. An example for such a setting is voting records of legislators on different issues, such as defense, energy, and healthcare. We develop a Markov graphical model to characterize the heterogeneous dependence structures arising from such data. The model is fitted via a joint estimation method that preserves the underlying common graph structure, but also allows for differences between the networks. The method employs a group penalty that targets the common zero interaction effects across all the networks. We apply the method to describe the internal networks of the U.S. Senate on several important issues. Our analysis reveals individual structure for each issue, distinct from the underlying well-known bipartisan structure common to all categories which we are able to extract separately. We also establish consistency of the proposed method both for parameter estimation and model selection, and evaluate its numerical performance on a number of simulated examples.

This paper proposes a joint model for longitudinal binary and count outcomes. We apply the model to a unique longitudinal study of teen driving where risky driving behavior and the occurrence of crashes or near crashes are measured prospectively over the first 18 months of licensure. Of scientific interest is relating the two processes and predicting crash and near crash outcomes. We propose a two-state mixed hidden Markov model whereby the hidden state characterizes the mean for the joint longitudinal crash/near crash outcomes and elevated g-force events which are a proxy for risky driving. Heterogeneity is introduced in both the conditional model for the count outcomes and the hidden process using a shared random effect. An estimation procedure is presented using the forward–backward algorithm along with adaptive Gaussian quadrature to perform numerical integration. The estimation procedure readily yields hidden state probabilities as well as providing for a broad class of predictors.

Multi-species distribution modeling, which relates the occurrence of multiple species to environmental variables, is an important tool used by ecologists for both predicting the distribution of species in a community and identifying the important variables driving species co-occurrences. Recently, Dunstan, Foster and Darnell [ Ecol. Model. 222 (2011) 955–963] proposed using finite mixture of regression (FMR) models for multi-species distribution modeling, where species are clustered based on their environmental response to form a small number of “archetypal responses.” As an illustrative example, they applied their mixture model approach to a presence–absence data set of 200 marine organisms, collected along the Great Barrier Reef in Australia. Little attention, however, was given to the problem of model selection—since the archetypes (mixture components) may depend on different but likely overlapping sets of covariates, a method is needed for performing variable selection on all components simultaneously. In this article, we consider using penalized likelihood functions for variable selection in FMR models. We propose two penalties which exploit the grouped structure of the covariates, that is, each covariate is represented by a group of coefficients, one for each component. This leads to an attractive form of shrinkage that allows a covariate to be removed from all components simultaneously. Both penalties are shown to possess specific forms of variable selection consistency, with simulations indicating they outperform other methods which do not take into account the grouped structure. When applied to the Great Barrier Reef data set, penalized FMR models offer more insight into the important variables driving species co-occurrence in the marine community (compared to previous results where no model selection was conducted), while offering a computationally stable method of modeling complex species–environment relationships (through regularization).

Without measurement errors in predictors, discontinuity of a nonparametric regression function at unknown locations could be estimated using a number of existing approaches. However, it becomes a challenging problem when the predictors contain measurement errors. In this paper, an error-in-variables jump point estimator is suggested for a nonparametric generalized error-in-variables regression model. A major feature of our method is that it does not impose any parametric distribution on the measurement error. Its performance is evaluated by both numerical studies and theoretical justifications. The method is applied to studying the impact of Medicare Levy Surcharge on the private health insurance take-up rate in Australia.

We introduce hmmSeq, a model-based hierarchical Bayesian technique for detecting differentially expressed genes from RNA-seq data. Our novel hmmSeq methodology uses hidden Markov models to account for potential co-expression of neighboring genes. In addition, hmmSeq employs an integrated approach to studies with technical or biological replicates, automatically adjusting for any extra-Poisson variability. Moreover, for cases when paired data are available, hmmSeq includes a paired structure between treatments that incoporates subject-specific effects. To perform parameter estimation for the hmmSeq model, we develop an efficient Markov chain Monte Carlo algorithm. Further, we develop a procedure for detection of differentially expressed genes that automatically controls false discovery rate. A simulation study shows that the hmmSeq methodology performs better than competitors in terms of receiver operating characteristic curves. Finally, the analyses of three publicly available RNA-seq data sets demonstrate the power and flexibility of the hmmSeq methodology. An R package implementing the hmmSeq framework will be submitted to CRAN upon publication of the manuscript.

We focus on the biological problem of tracking organelles as they move through cells. In the past, most intracellular movements were recorded manually, however, the results are too incomplete to capture the full complexity of organelle motions. An automated tracking algorithm promises to provide a complete analysis of noisy microscopy data. In this paper, we adopt statistical techniques from a Bayesian random set point of view. Instead of considering each individual organelle, we examine a random set whose members are the organelle states and we establish a Bayesian filtering algorithm involving such set states. The propagated multi-object densities are approximated using a Gaussian mixture scheme. Our algorithm is applied to synthetic and experimental data.

To study how a zygote develops into an embryo with different tissues, large-scale 4D confocal movies of C. elegans embryos have been produced recently by experimental biologists. However, the lack of principled statistical methods for the highly noisy data has hindered the comprehensive analysis of these data sets. We introduced a probabilistic change point model on the cell lineage tree to estimate the embryonic gene expression onset time. A Bayesian approach is used to fit the 4D confocal movies data to the model. Subsequent classification methods are used to decide a model selection threshold and further refine the expression onset time from the branch level to the specific cell time level. Extensive simulations have shown the high accuracy of our method. Its application on real data yields both previously known results and new findings.

Understanding which phenotypic traits are consistently correlated throughout evolution is a highly pertinent problem in modern evolutionary biology. Here, we propose a multivariate phylogenetic latent liability model for assessing the correlation between multiple types of data, while simultaneously controlling for their unknown shared evolutionary history informed through molecular sequences. The latent formulation enables us to consider in a single model combinations of continuous traits, discrete binary traits and discrete traits with multiple ordered and unordered states. Previous approaches have entertained a single data type generally along a fixed history, precluding estimation of correlation between traits and ignoring uncertainty in the history. We implement our model in a Bayesian phylogenetic framework, and discuss inference techniques for hypothesis testing. Finally, we showcase the method through applications to columbine flower morphology, antibiotic resistance in Salmonella and epitope evolution in influenza.

The Rényi index (RI) is a one-parameter class of indices that summarize health disparities among population groups by measuring divergence between the distributions of disease burden and population shares of these groups. The rank-dependent RI introduced in this paper is a two-parameter class of health disparity indices that also accounts for the association between socioeconomic rank and health; it may be derived from a rank-dependent social welfare function. Two competing classes are discussed and the rank-dependent RI is shown to be more robust to changes in the distribution of either socioeconomic rank or health. The standard error and sampling distribution of the rank-dependent RI are evaluated using linearization and resampling techniques, and the methodology is illustrated using health survey data from the U.S. National Health and Nutrition Examination Survey and registry data from the U.S. Surveillance, Epidemiology and End Results Program. Such data underlie many population-based objectives within the U.S. Healthy People 2020 initiative. The rank-dependent RI provides a unified mathematical framework for eliciting various societal positions with regards to the policies that are tied to such wide-reaching public health initiatives. For example, if population groups with lower socioeconomic position were ascertained to be more likely to utilize costly public programs, then the parameters of the RI could be selected to reflect prioritizing those population groups for intervention or treatment.

We propose a generic Bayesian framework for inference in distributional regression models in which each parameter of a potentially complex response distribution and not only the mean is related to a structured additive predictor. The latter is composed additively of a variety of different functional effect types such as nonlinear effects, spatial effects, random coefficients, interaction surfaces or other (possibly nonstandard) basis function representations. To enforce specific properties of the functional effects such as smoothness, informative multivariate Gaussian priors are assigned to the basis function coefficients. Inference can then be based on computationally efficient Markov chain Monte Carlo simulation techniques where a generic procedure makes use of distribution-specific iteratively weighted least squares approximations to the full conditionals. The framework of distributional regression encompasses many special cases relevant for treating nonstandard response structures such as highly skewed nonnegative responses, overdispersed and zero-inflated counts or shares including the possibility for zero- and one-inflation. We discuss distributional regression along a study on determinants of labour incomes for full-time working males in Germany with a particular focus on regional differences after the German reunification. Controlling for age, education, work experience and local disparities, we estimate full conditional income distributions allowing us to study various distributional quantities such as moments, quantiles or inequality measures in a consistent manner in one joint model. Detailed guidance on practical aspects of model choice including the selection of several competing distributions for labour incomes and the consideration of different covariate effects on the income distribution complete the distributional regression analysis. We find that next to a lower expected income, full-time working men in East Germany also face a more unequal income distribution than men in the West, ceteris paribus.

The objective of many high-dimensional microarray and RNA-seq studies is to develop a classifier of cancer patients based on characteristics of their disease. The germinal center B-cell (GCB) classifier study in lymphoma and the National Cancer Institute’s Director’s Challenge lung (DC-lung) study are two examples. In recent years, such classifiers are often developed using regularized regression, such as the lasso. A critical question is whether a better classifier can be developed from a larger training set size and, if so, how large the training set should be. This paper examines these two questions using an existing sample size method and a novel sample size method developed here specifically for lasso logistic regression. Both methods are based on pilot data. We reexamine the lymphoma and lung cancer data sets to evaluate the sample sizes, and use resampling to assess the estimation methods. We also study application to an RNA-seq data set. We find that it is feasible to estimate sample size for regularized logistic regression if an adequate pilot data set exists. The GCB and the DC-lung data sets appear adequate, under specific assumptions. Existing human RNA-seq data sets are by and large inadequate, and cannot be used as pilot data. Pilot RNA-seq data can be simulated, and the methods in this paper can be used for sample size estimation. A MATLAB program is made available.

An increasingly important goal of psychiatry is the use of brain imaging data to develop predictive models. Here we present two contributions to statistical methodology for this purpose. First, we propose and compare a set of wavelet-domain procedures for fitting generalized linear models with scalar responses and image predictors: sparse variants of principal component regression and of partial least squares, and the elastic net. Second, we consider assessing the contribution of image predictors over and above available scalar predictors, in particular, via permutation tests and an extension of the idea of confounding to the case of functional or image predictors. Using the proposed methods, we assess whether maps of a spontaneous brain activity measure, derived from functional magnetic resonance imaging, can meaningfully predict presence or absence of attention deficit/hyperactivity disorder (ADHD). Our results shed light on the role of confounding in the surprising outcome of the recent ADHD-200 Global Competition, which challenged researchers to develop algorithms for automated image-based diagnosis of the disorder.