Medical Sciences Commons^™

Cross-Validation And Hypothesis Testing In Neuroimaging: An Irenic Comment On The Exchange Between Friston And Lindquist Et Al., Philip T. Reiss

Philip T. Reiss

The “ten ironic rules for statistical reviewers” presented by Friston (2012) prompted a rebuttal by Lindquist et al. (2013), which was followed by a rejoinder by Friston (2013). A key issue left unresolved in this discussion is the use of cross-validation to test the significance of predictive analyses. This note discusses the role that cross-validation-based and related hypothesis tests have come to play in modern data analyses, in neuroimaging and other fields. It is shown that such tests need not be suboptimal and can fill otherwise-unmet inferential needs.

Can Acute Dermal Systemic Toxicity Tests Be Replaced With Oral Tests? A Comparison Of Route-Specific Systemic Toxicity And Hazard Classifications Under The Globally Harmonized System Of Classification And Labelling Of Chemicals (Ghs), Nigel P. Moore, David J. Andrew, Donald L. Bjerke, Stuart Creton, David Dreher, Thomas Holmes, Pilar Prieto, Troy Seidle, Tim G. Rowan

Troy Seidle, PhD

Acute systemic toxicity data (LD50 values) and hazard classifications derived in the rat following oral administration and dermal application have been analysed to examine whether or not orally-derived hazard classification or LD50 values can be used to determine dermal hazard classification. Comparing the oral and dermal classifications for 335 substances derived from oral and dermal LD50 values respectively revealed 17% concordance, and indicated that 7% of substances would be classified less severely while 76% would be classified more severely if oral classifications were applied directly to the dermal route. In contrast, applying the oral LD50 values within the dermal classification …

Massively Parallel Nonparametric Regression, With An Application To Developmental Brain Mapping, Philip T. Reiss, Lei Huang, Yin-Hsiu Chen, Lan Huo, Thaddeus Tarpey, Maarten Mennes

Lei Huang

We propose a penalized spline approach to performing large numbers of parallel nonparametric analyses of either of two types: restricted likelihood ratio tests of a parametric regression model versus a general smooth alternative, and nonparametric regression. Compared with naively performing each analysis in turn, our techniques reduce computation time dramatically. Viewing the large collection of scatterplot smooths produced by our methods as functional data, we develop a clustering approach to summarize and visualize these results. Our approach is applicable to ultra-high-dimensional data, particularly data acquired by neuroimaging; we illustrate it with an analysis of developmental trajectories of functional connectivity at …

Evaluation Of Student Outcomes In Online Vs. Campus Biostatistics Education In A Graduate School Of Public Health, John Mcgready, Ron Brookmeyer

Ron Brookmeyer

Objective: To compare student outcomes between concurrent online and on-campus sections of an introductory biostatistics course offered at a U.S. school of public health in 2005. Methods: Enrolled students (95 online, 92 on-campus) were invited to participate in a confidential online survey. The course outcomes were compared between the two sections adjusting for differences in student characteristics. Results: Seventy-two online (76%) and 66 (72%) on-campus enrollees participated. Unadjusted final exam scores for the online and on-campus sections were respectively 85.1 and 86.3 (p = 0.50) in term 1, and 87.7 and 86.9 (p=0.58) in term 2. After adjustment for student …

Estimation Of Hiv Incidence Using Multiple Biomakers, Ron Brookmeyer, Jacob Konikoff, Oliver Laeyendecker, Susan Eshleman

Ron Brookmeyer

The incidence of human immunodeficiency virus (HIV) is the rate at which new HIV infections occur in populations. The development of accurate, practical, and cost-effective approaches to estimation of HIV incidence is a priority among researchers in HIV surveillance because of limitations with existing methods. In this paper, we develop methods for estimating HIV incidence rates using multiple biomarkers in biological samples collected from a cross-sectional survey. An advantage of the method is that it does not require longitudinal follow-up of individuals. We use assays for BED, avidity, viral load, and CD4 cell count data from clade B samples collected …

Varying-Smoother Models For Functional Responses, Philip T. Reiss, Lei Huang, Huaihou Chen, Stan Colcombe

Philip T. Reiss

This paper studies estimation of a smooth function f(x,v) when we are given functional responses of the form f(x, ·) + error, but scientific interest centers on the collection of functions f(·,v) for different v. The motivation comes from studies of human brain development, in which x denotes age whereas v refers to brain locations. Analogously to varying-coefficient models, in which the mean response is linear in x, the “varying-smoother” models that we consider exhibit nonlinear dependence on x that varies smoothly with v. We discuss three approaches to estimating varying-smoother models: (a) methods that employ a tensor product penalty; …

Paradoxical Results Of Adaptive False Discovery Rate Procedures In Neuroimaging Studies, Philip T. Reiss, Armin Schwartzman, Feihan Lu, Lei Huang, Erika Proal

Philip T. Reiss

Adaptive false discovery rate (FDR) procedures, which offer greater power than the original FDR procedure of Benjamini and Hochberg, are often applied to statistical maps of the brain. When a large proportion of the null hypotheses are false, as in the case of widespread effects such as cortical thinning throughout much of the brain, adaptive FDR methods can surprisingly reject more null hypotheses than not accounting for multiple testing at all—i.e., using uncorrected p-values. A straightforward mathematical argument is presented to explain why this can occur with the q-value method of Storey and colleagues, and a simulation study shows that …

Technology Assessment Of Automated Atlas Based Segmentation In Prostate Bed Contouring, Jeremiah Hwee, Alexander Louie, Stewart Gaede, Glenn Bauman, David D'Souza, Tracy Sexton, Michael Lock, Belal Ahmad, George Rodrigues

Michael Lock

BACKGROUND: Prostate bed (PB) contouring is time consuming and associated with inter-observer variability. We evaluated an automated atlas-based segmentation (AABS) engine in its potential to reduce contouring time and inter-observer variability.

METHODS: An atlas builder (AB) manually contoured the prostate bed, rectum, left femoral head (LFH), right femoral head (RFH), bladder, and penile bulb of 75 post-prostatectomy cases to create an atlas according to the recent RTOG guidelines. 5 other Radiation Oncologists (RO) and the AABS contoured 5 new cases. A STAPLE contour for each of the 5 patients was generated. All contours were anonymized and sent back to the …

Function-On-Scalar Regression With The Refund Package, Philip T. Reiss

Philip T. Reiss

No abstract provided.

Smoothness Selection For Penalized Quantile Regression Splines, Philip T. Reiss, Lei Huang

Philip T. Reiss

Modern data-rich analyses may call for fitting a large number of nonparametric quantile regressions. For example, growth charts may be constructed for each of a collection of variables, to identify those for which individuals with a disorder tend to fall in the tails of their age-specific distribution; such variables might serve as developmental biomarkers. When such analyses are carried out by penalized spline smoothing, reliable automatic selection of the smoothing parameter is particularly important. We show that two popular methods for smoothness selection may tend to overfit when estimating extreme quantiles as a smooth function of a predictor such as …

Semiparametric Methods For Mapping Brain Development, Philip T. Reiss, Yin-Hsiu Chen, Lan Huo

Philip T. Reiss

No abstract provided.

Introducing Functional Data Analysis To Neuroimaging, And Vice Versa, Philip T. Reiss

Philip T. Reiss

No abstract provided.

Massively Parallel Nonparametrics [Hds 2011 Slides], Philip T. Reiss, Lei Huang

Philip T. Reiss

No abstract provided.

Flexible Dependence Of Functional Responses On Scalar Predictors, Philip T. Reiss, Lei Huang

Philip T. Reiss

No abstract provided.

Extracting Information From Functional Connectivity Maps Via Function-On-Scalar Regression, Philip T. Reiss, Maarten Mennes, Eva Petkova, Lei Huang, Matthew J. Hoptman, Bharat B. Biswal, Stanley J. Colcombe, Xi-Nian Zuo, Michael P. Milham

Lei Huang

Functional connectivity of an individual human brain is often studied by acquiring a resting state functional magnetic resonance imaging scan, and mapping the correlation of each voxel's BOLD time series with that of a seed region. As large collections of such maps become available, including multisite data sets, there is an increasing need for ways to distill the information in these maps in a readily visualized form. Here we propose a two-step analytic strategy. First, we construct connectivity-distance profiles, which summarize the connectivity of each voxel in the brain as a function of distance from the seed, a functional relationship …

National Estimates Of The Prevalence Of Alzheimer's Disease In The United States, Ron Brookmeyer, Denis Evans, Liesi Hebert, Langa Kenneth, Heeringa Steven, Plassman Brenda, Kukull Kenneth

Ron Brookmeyer

Several methods of estimating prevalence of dementia are presented in this article. For both Brookmeyer and the Chicago Health and Aging project (CHAP), the estimates of prevalence are derived statistically, forward calculating from incidence and survival figures. The choice of incidence rates on which to build the estimates may be critical. Brookmeyer used incidence rates from several published studies, whereas the CHAP investigators applied the incidence rates observed in their own cohort. The Aging, Demographics, and Memory Study (ADAMS) and the East Boston Senior Health Project (EBSHP) were sample surveys designed to ascertain the prevalence of Alzheimer’s disease and dementia. …

Statistical Considerations In Determining Hiv Incidence From Changes In Hiv Prevalence, Ron Brookmeyer, Jacob Konikoff

Ron Brookmeyer

The development of methods for estimating HIV incidence is critical for tracking the epidemic and for designing, targeting and evaluating HIV prevention efforts. One method for estimating incidence is based on changes in HIV prevalence. That method is attracting increased attention because national population-based HIV prevalence surveys, such as Demographic and Health Surveys, are being conducted throughout the world. Here, we consider some statistical issues associated with estimating HIV incidence from two population-based HIV prevalence surveys conducted at two different points in time. We show that the incidence estimator depends on the relative survival rate. We evaluate the sensitivity of …

Extracting Information From Functional Connectivity Maps Via Function-On-Scalar Regression, Philip T. Reiss, Maarten Mennes, Eva Petkova, Lei Huang, Matthew J. Hoptman, Bharat B. Biswal, Stanley J. Colcombe, Xi-Nian Zuo, Michael P. Milham

Philip T. Reiss

Functional connectivity of an individual human brain is often studied by acquiring a resting state functional magnetic resonance imaging scan, and mapping the correlation of each voxel's BOLD time series with that of a seed region. As large collections of such maps become available, including multisite data sets, there is an increasing need for ways to distill the information in these maps in a readily visualized form. Here we propose a two-step analytic strategy. First, we construct connectivity-distance profiles, which summarize the connectivity of each voxel in the brain as a function of distance from the seed, a functional relationship …

Fast, Flexible Function-On-Scalar Regression, With An Application To Brain Development, Philip T. Reiss, Lei Huang

Philip T. Reiss

No abstract provided.

On Distance-Based Permutation Tests For Between-Group Comparisons, Philip T. Reiss, M. Henry H. Stevens, Zarrar Shehzad, Eva Petkova, Michael P. Milham

Philip T. Reiss

Permutation tests based on distances among multivariate observations have found many applications in the biological sciences. Two major testing frameworks of this kind are multiresponse permutation procedures and pseudo-F tests arising from a distance-based extension of multivariate analysis of variance. In this paper we derive conditions under which these two frameworks are equivalent. The methods and equivalence results are illustrated by reanalyzing an ecological data set and by a novel application to functional magnetic resonance imaging data.

Functional Generalized Linear Models With Images As Predictors, Philip T. Reiss, R. Todd Ogden

Philip T. Reiss

Functional principal component regression (FPCR) is a promising new method for regressing scalar outcomes on functional predictors. In this paper we present a theoretical justification for the use of principal components in functional regression. FPCR is then extended in two directions: from linear to the generalized linear modeling, and from univariate signal predictors to high-resolution image predictors. We show how to implement the method efficiently by adapting generalized additive model technology to the functional regression context. A technique is proposed for estimating simultaneous confidence bands for the coefficient function; in the neuroimaging setting, this yields a novel means to identify …

Measuring The Hiv/Aids Epidemic: Approaches And Challenges, Ron Brookmeyer

Ron Brookmeyer

In this article, the author reviews current approaches and methods for measuring the scope of the human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) epidemic and their strengths and weaknesses. In recent years, various public health agencies have revised statistical estimates of the scope of the HIV/AIDS pandemic. The author considers the reasons underlying these revisions. New sources of data for estimating HIV prevalence have become available, such as nationally representative probability-based surveys. New technologies such as biomarkers that indicate when persons became infected are now used to determine HIV incidence rates. The author summarizes the main sources of errors and …

On The Statistical Accuracy Of Biomarker Assays Of Hiv Incidence, Ron Brookmeyer

Ron Brookmeyer

Objective: To evaluate the statistical accuracy of estimates of current HIV incidence rates from cross-sectional surveys, and to identify characteristics of assays that improve accuracy.

Methods: Performed mathematical and statistical analysis of the cross-sectional estimator of HIV incidence to evaluate bias and variance. Developed probability models to evaluate impact of long tails of the window period distribution on accuracy.

Results: The standard cross-sectional estimate of HIV incidence rate is estimating a time-lagged incidence where the lag time, called the shadow, depends on the mean and the coefficient of variation of window periods. Equations show how the shadow increases with the …

Semiparametric Analysis Of Recurrent Events: Artificial Censoring, Truncation, Pairwise Estimation And Inference, Debashis Ghosh

Debashis Ghosh

The analysis of recurrent failure time data from longitudinal studies can be complicated by the presence of dependent censoring. There has been a substantive literature that has developed based on an artificial censoring device. We explore in this article the connection between this class of methods with truncated data structures. In addition, a new procedure is developed for estimation and inference in a joint model for recurrent events and dependent censoring. Estimation proceeds using a mixed U-statistic based estimating function approach. New resampling-based methods for variance estimation and model checking are also described. The methods are illustrated by application to …

Multiple Loci Within The Major Histocompatibility Complex Confer Risk Of Psoriasis, Bing-Jian Feng, Liang-Dan Sun, Razieh Soltani-Arabshahi, Anne M. Bowcock, Rajan P. Nair, Philip Stuart, James T. Elder, Steven J. Schrodi, Ann B. Begovich, Goncalo R. Abecasis, Xue-Jun Zhang, Kristina P. Callis Duffin, Gerald G. Krueger, David E. Goldgar

Steven J Schrodi

Psoriasis is a common inflammatory skin disease characterized by thickened scaly red plaques. Previously we have performed a genome-wide association study (GWAS) on psoriasis with 1,359 cases and 1,400 controls, which were genotyped for 447,249 SNPs. The most significant finding was for SNP rs12191877, which is in tight linkage disequilibrium with HLA-Cw*0602, the consensus risk allele for psoriasis. However, it is not known whether there are other psoriasis loci within the MHC in addition to HLA-C. In the present study, we searched for additional susceptibility loci within the human leukocyte antigen (HLA) region through in-depth analyses of the GWAS data; …

Regression When The Predictors Are Images, Philip T. Reiss

Philip T. Reiss

No abstract provided.

Smoothing Parameter Selection For A Class Of Semiparametric Linear Models, Philip T. Reiss, R. Todd Ogden

Philip T. Reiss

Spline-based approaches to nonparametric and semiparametric regression, as well as to regression of scalar outcomes on functional predictors, entail choosing a parameter controlling the extent to which roughness of the fitted function is penalized. In this paper we demonstrate that the equations determining two popular methods for smoothing parameter selection, generalized cross-validation and restricted maximum likelihood, share a similar form that allows us to prove several results common to both, and to derive a condition under which they yield identical values. These ideas are illustrated by application of functional principal component regression, a method for regressing scalars on functions, to …

Should Biomarker Estimates Of Hiv Incidence Be Adjusted?, Ron Brookmeyer

Ron Brookmeyer

Objective: To evaluate adjustment procedures that have been proposed to correct HIV incidence rates derived from cross-sectional surveys of biomarkers (BED). These procedures were motivated by some reports that the biomarker BED approach overestimates incidence when compared to cohort studies.

Design: Considered the Hargrove and McDougal adjustment procedures that adjust biomarker estimates of HIV incidence rates for misclassification with respect to the timing of infections.

Methods: Performed mathematical and statistical analysis of the adjustment formulas. Evaluated sources of error in cohort studies of incidence that could also explain discrepancies between cohort and biomarker estimates.

Results: The McDougal adjustment has no …

The Effects Of Herd Immunity On The Power Of Vaccine Trials, Blake Charvat, Ron Brookmeyer, Jay Herson

Ron Brookmeyer

We evaluate the effects of herd immunity on the power of vaccine trials. We consider large-scale trials in which persons are individually randomized to either placebo or vaccine. We evaluate the adequacy of naive power calculations that ignore the effects of herd immunity such as those based on the comparison of two independent binomials. We developed a simulation design to evaluate the quantitative effects of herd immunity on power. The simulation design accounted for nonhomogeneous mixing. We found that naive power calculations that ignore the effects of herd immunity can seriously overestimate power. In fact, we found that as sample …

Genome-Wide Scan Reveals Association Of Psoriasis With Il-23 And Nf-B Pathways, Rajan P. Nair, Kristina C. Duffin, Cynthia Helms, Jun Ding, Philip E. Stuart, David Goldgar, Johann E. Gudjonsson, Yun Li, Trilokraj Tejasvi, Bing-Jiag Feng, Andreas Ruether, Stefan Schreiber, Michael Weichenthal, Dafna Gladman, Proton Rahman, Steven J. Schrodi, Sampath Prahalad, Stephen L. Guthery, Judith Fischer, Wilson Liao, Pui-Yan Kwok, Alan Menter, G Mark Lathrop, Carol A. Wise, Ann B. Begovich, John J. Voorhees, James T. Elder, Gerald G. Krueger, Anne M. Bowcock, Goncalo R. Abecasis

Steven J Schrodi

Psoriasis is a common immune-mediated disorder that affects the skin, nails and joints. To identify psoriasis susceptibility loci, we genotyped 438,670 SNPs in 1,409 psoriasis cases and 1,436 controls of European ancestry. We followed up 21 promising SNPs in 5,048 psoriasis cases and 5,041 controls. Our results provide strong support for the association of at least seven genetic loci and psoriasis (each with combined P < 5 10-8). Loci with confirmed association include HLA-C, three genes involved in IL-23 signaling (IL23A, IL23R, IL12B), two genes that act downstream of TNF- and regulate NF-B signaling (TNIP1, TNFAIP3) and two genes involved in the modulation of Th2 immune responses (IL4, IL13). Although the proteins encoded in these loci are known to interact biologically, we found no evidence for epistasis between associated SNPs. Our results expand the catalog of genetic loci implicated in psoriasis susceptibility and suggest priority targets for study in other auto-immune disorders.