Grant Number:	5R01CA085848-15 Interpret this number
Primary Investigator:	Davidian, Marie
Organization:	North Carolina State University Raleigh
Project Title:	Flexible Statistical Methods for Biomedical Data
Fiscal Year:	2015

DESCRIPTION (provided by applicant): An ongoing challenge in health sciences research is the development of statistical models used to study relationships between subject characteristics and interventions and disease onset, recurrence, and progression and other health outcomes. This enterprise has become considerably more complex as new technologies, the quest to discover new biomarkers, and improved resources for handling vast repositories of data have led to the collection of high-dimensional information, and there has been extensive research on formal methods for identifying important prognostic variables to include in a model to be used, e.g., to assess population risk. The objective of the first two specific aims of this renewal application is to develop new methods for such variable selection in model-building. Many key health status variables collected in studies of chronic disease, e.g., blood pressure or serum biomarker levels, are imprecise measurements of a "true" quantity relevant to understanding risk, such as long-term blood pressure. The first aim is to develop methods for variable selection when some such covariates are subject to such measurement error. Linear and generalized linear models for independent data and their mixed-effects counterparts for longitudinal and other clustered data are widely used, but these parametric models may not be sufficiently flexible to approximate the complex relationships involved. The second aim is to extend advances made in our previous project period toward new methods for simultaneous parameter estimation and variable selection in more flexible semiparametric such models to develop new techniques that allow for arbitrary numbers of both parametric and nonparametric covariate effects, general outcome variables (e.g., continuous, binary), and adaptive identification of such effects. A key objective in many stud- ies is to elucidate the association between features of longitudinal profiles of biomarkers or other continuous measures and a primary health outcome using so-called joint models. Standard joint models represent the subject-specific profiles via a mixed-effects model, e.g., as straight lines with random subject-specific intercepts and slopes, whose random parameters are included as covariates in a model for the primary outcome. In some settings, interest may focus on the association between outcome and not only features such as slopes but also intra-subject variation in the longitudinal measure. The third aim is to develop new methods for joint models involving both random intra-subject mean and variance parameters, exploiting techniques developed in the previous project period. Many longitudinal measures are censored due to limits of quantification of the assay used in their determination, and longitudinal analysis must take this into appropriate account. Our fourth aim focuses on development of new methods for mixed-effects models that address not only this issue but draw on work in previous project periods to relax the usual normality assumption on random effects and yield an estimate of their density, providing the analyst with a tool for exploring underlying features of the population.




Survival Benefit of Lung Transplantation in the Modern Era of Lung Allocation.
Authors: Vock D.M. , Durheim M.T. , Tsuang W.M. , Finlen Copeland C.A. , Tsiatis A.A. , Davidian M. , Neely M.L. , Lederer D.J. , Palmer S.M. .
Source: Annals Of The American Thoracic Society, 2017 02; 14(2), p. 172-181.
PMID: 27779905
Related Citations

The analysis of multivariate longitudinal data: A review.
Authors: Verbeke G. , Fieuws S. , Molenberghs G. , Davidian M. .
Source: Statistical Methods In Medical Research, 2017 Feb; 26(1), p. 112.
PMID: 28054505
Related Citations

Interactive Q-learning for Quantiles.
Authors: Linn K.A. , Laber E.B. , Stefanski L.A. .
Source: Journal Of The American Statistical Association, 2017; 112(518), p. 638-649.
EPub date: 2017-03-31 00:00:00.0.
PMID: 28890584
Related Citations

Variable Selection in Kernel Regression Using Measurement Error Selection Likelihoods.
Authors: White K.R. , Stefanski L.A. , Wu Y. .
Source: Journal Of The American Statistical Association, 2017; 112(520), p. 1587-1597.
EPub date: 2017-07-19 00:00:00.0.
PMID: 29628539
Related Citations

Bivariate Mixed Effects Analysis of Clustered Data with Large Cluster Sizes.
Authors: Zhang D. , Sun J.L. , Pieper K. .
Source: Statistics In Biosciences, 2016 Oct; 8(2), p. 220-233.
PMID: 27746847
Related Citations

A flexible model for correlated medical costs, with application to medical expenditure panel survey data.
Authors: Chen J. , Liu L. , Shih Y.C. , Zhang D. , Severini T.A. .
Source: Statistics In Medicine, 2016-03-15 00:00:00.0; 35(6), p. 883-94.
EPub date: 2016-03-15 00:00:00.0.
PMID: 26403805
Related Citations

Properties of Estimators in Exponential Family Settings with Observation-based Stopping Rules.
Authors: Milanzi E. , Molenberghs G. , Alonso A. , Kenward M.G. , Verbeke G. , Tsiatis A.A. , Davidian M. .
Source: Journal Of Biometrics & Biostatistics, 2016 Feb; 7(1), .
PMID: 27175309
Related Citations

Using decision lists to construct interpretable and parsimonious treatment regimes.
Authors: Zhang Y. , Laber E.B. , Tsiatis A. , Davidian M. .
Source: Biometrics, 2015 Dec; 71(4), p. 895-904.
PMID: 26193819
Related Citations

Estimation After a Group Sequential Trial.
Authors: Milanzi E. , Molenberghs G. , Alonso A. , Kenward M.G. , Tsiatis A.A. , Davidian M. , Verbeke G. .
Source: Statistics In Biosciences, 2015 Oct; 7(2), p. 187-205.
PMID: 26478751
Related Citations

A Fast EM Algorithm for Fitting Joint Models of a Binary Response and Multiple Longitudinal Covariates Subject to Detection Limits.
Authors: Bernhardt P.W. , Zhang D. , Wang H.J. .
Source: Computational Statistics & Data Analysis, 2015-05-01 00:00:00.0; 85, p. 37-53.
PMID: 25598564
Related Citations

Statistical Methods for Generalized Linear Models with Covariates Subject to Detection Limits.
Authors: Bernhardt P.W. , Wang H.J. , Zhang D. .
Source: Statistics In Biosciences, 2015 May; 7(1), p. 68-89.
PMID: 26257836
Related Citations

Response to reader reaction.
Authors: Zhang B. , Tsiatis A.A. , Laber E.B. , Davidian M. .
Source: Biometrics, 2015 Mar; 71(1), p. 271-3.
PMID: 25355405
Related Citations

Assessing gene-environment interactions for common and rare variants with binary traits using gene-trait similarity regression.
Authors: Zhao G. , Marceau R. , Zhang D. , Tzeng J.Y. .
Source: Genetics, 2015 Mar; 199(3), p. 695-710.
PMID: 25585620
Related Citations

Q- and A-learning Methods for Estimating Optimal Dynamic Treatment Regimes.
Authors: Schulte P.J. , Tsiatis A.A. , Laber E.B. , Davidian M. .
Source: Statistical Science : A Review Journal Of The Institute Of Mathematical Statistics, 2014 Nov; 29(4), p. 640-661.
PMID: 25620840
Related Citations

Interactive model building for Q-learning.
Authors: Laber E.B. , Linn K.A. , Stefanski L.A. .
Source: Biometrika, 2014-10-20 00:00:00.0; 101(4), p. 831-847.
PMID: 25541562
Related Citations

Probability-enhanced sufficient dimension reduction for binary classification.
Authors: Shin S.J. , Wu Y. , Zhang H.H. , Liu Y. .
Source: Biometrics, 2014 Sep; 70(3), p. 546-55.
PMID: 24779683
Related Citations

Discussion of "Combining biomarkers to optimize patient treatment recommendation".
Authors: Laber E.B. , Tsiatis A.A. , Davidian M. , Holloway S.T. .
Source: Biometrics, 2014 Sep; 70(3), p. 707-10.
PMID: 24888979
Related Citations

Structured functional additive regression in reproducing kernel Hilbert spaces.
Authors: Zhu H. , Yao F. , Zhang H.H. .
Source: Journal Of The Royal Statistical Society. Series B, Statistical Methodology, 2014-06-01 00:00:00.0; 76(3), p. 581-603.
PMID: 25013362
Related Citations

Two-Dimensional Solution Surface for Weighted Support Vector Machines.
Authors: Shin S.J. , Wu Y. , Zhang H.H. .
Source: Journal Of Computational And Graphical Statistics : A Joint Publication Of American Statistical Association, Institute Of Mathematical Statistics, Interface Foundation Of North America, 2014-04-03 00:00:00.0; 23(2), p. 383-402.
PMID: 24955001
Related Citations

On random sample size, ignorability, ancillarity, completeness, separability, and degeneracy: sequential trials, random sample sizes, and missing data.
Authors: Molenberghs G. , Kenward M.G. , Aerts M. , Verbeke G. , Tsiatis A.A. , Davidian M. , Rizopoulos D. .
Source: Statistical Methods In Medical Research, 2014 Feb; 23(1), p. 11-41.
PMID: 22514029
Related Citations

The analysis of multivariate longitudinal data: a review.
Authors: Verbeke G. , Fieuws S. , Molenberghs G. , Davidian M. .
Source: Statistical Methods In Medical Research, 2014 Feb; 23(1), p. 42-59.
PMID: 22523185
Related Citations

Adaptive Elastic Net for Generalized Methods of Moments.
Authors: Caner M. , Zhang H.H. .
Source: Journal Of Business & Economic Statistics : A Publication Of The American Statistical Association, 2014-01-30 00:00:00.0; 32(1), p. 30-47.
PMID: 24570579
Related Citations

Flexible Modeling of Survival Data with Covariates Subject to Detection Limits via Multiple Imputation.
Authors: Bernhardt P.W. , Wang H.J. , Zhang D. .
Source: Computational Statistics & Data Analysis, 2014 Jan; 69, .
PMID: 24204085
Related Citations

SNP_NLMM: A SAS Macro to Implement a Flexible Random Effects Density for Generalized Linear and Nonlinear Mixed Models.
Authors: Vock D.M. , Davidian M. , Tsiatis A.A. .
Source: Journal Of Statistical Software, 2014-01-01 00:00:00.0; 56, p. 2.
PMID: 24688453
Related Citations

Variable Selection in Nonparametric Classification via Measurement Error Model Selection Likelihoods.
Authors: Stefanski L.A. , Wu Y. , White K. .
Source: Journal Of The American Statistical Association, 2014; 109(506), p. 574-589.
PMID: 24976661
Related Citations

Interaction Screening for Ultra-High Dimensional Data.
Authors: Hao N. , Zhang H.H. .
Source: Journal Of The American Statistical Association, 2014; 109(507), p. 1285-1301.
PMID: 25386043
Related Citations

Assessing the causal effect of organ transplantation on the distribution of residual lifetime.
Authors: Vock D.M. , Tsiatis A.A. , Davidian M. , Laber E.B. , Tsuang W.M. , Finlen Copeland C.A. , Palmer S.M. .
Source: Biometrics, 2013 Dec; 69(4), p. 820-9.
PMID: 24128090
Related Citations

Moment Adjusted Imputation for Multivariate Measurement Error Data with Applications to Logistic Regression.
Authors: Thomas L. , Stefanski L.A. , Davidian M. .
Source: Computational Statistics & Data Analysis, 2013-11-01 00:00:00.0; 67, p. 15-24.
PMID: 24072947
Related Citations

A flexible model for the mean and variance functions, with application to medical cost data.
Authors: Chen J. , Liu L. , Zhang D. , Shih Y.C. .
Source: Statistics In Medicine, 2013-10-30 00:00:00.0; 32(24), p. 4306-18.
EPub date: 2013-10-30 00:00:00.0.
PMID: 23670952
Related Citations

Variable selection for optimal treatment decision.
Authors: Lu W. , Zhang H.H. , Zeng D. .
Source: Statistical Methods In Medical Research, 2013 Oct; 22(5), p. 493-504.
PMID: 22116341
Related Citations

Consistent Group Identification and Variable Selection in Regression with Correlated Predictors.
Authors: Sharma D.B. , Bondell H.D. , Zhang H.H. .
Source: Journal Of Computational And Graphical Statistics : A Joint Publication Of American Statistical Association, Institute Of Mathematical Statistics, Interface Foundation Of North America, 2013-04-01 00:00:00.0; 22(2), p. 319-340.
PMID: 23772171
Related Citations

Improved Sparse Multi-class Svm And Its Application For Gene Selection In Cancer Classification
Authors: Huang L. , Zhang H.H. , Zeng Z.B. , Bushel P.R. .
Source: Cancer Informatics, 2013; 12, p. 143-53.
PMID: 23966761
Related Citations

Efficient Robust Regression via Two-Stage Generalized Empirical Likelihood.
Authors: Bondell H.D. , Stefanski L.A. .
Source: Journal Of The American Statistical Association, 2013-01-01 00:00:00.0; 108(502), p. 644-655.
PMID: 23976805
Related Citations

Robust estimation of optimal dynamic treatment regimes for sequential treatment decisions.
Authors: Zhang B. , Tsiatis A.A. , Laber E.B. , Davidian M. .
Source: Biometrika, 2013; 100(3), .
PMID: 24302771
Related Citations

Variable selection for covariate-adjusted semiparametric inference in randomized clinical trials.
Authors: Yuan S. , Zhang H.H. , Davidian M. .
Source: Statistics In Medicine, 2012-12-20 00:00:00.0; 31(29), p. 3789-804.
EPub date: 2012-12-20 00:00:00.0.
PMID: 22733628
Related Citations

A robust method for estimating optimal treatment regimes.
Authors: Zhang B. , Tsiatis A.A. , Laber E.B. , Davidian M. .
Source: Biometrics, 2012 Dec; 68(4), p. 1010-8.
PMID: 22550953
Related Citations

Time-varying latent effect model for longitudinal data with informative observation times.
Authors: Cai N. , Lu W. , Zhang H.H. .
Source: Biometrics, 2012 Dec; 68(4), p. 1093-102.
PMID: 23025338
Related Citations

A Seminonparametric Approach to Joint Modeling of A Primary Binary Outcome and Longitudinal Data Measured at Discrete Informative Times.
Authors: Yan S. , Zhang D. , Lu W. , Grifo J.A. , Liu M. .
Source: Statistics In Biosciences, 2012-11-01 00:00:00.0; 4(2), p. 213-234.
PMID: 23259008
Related Citations

MOMENT-BASED METHOD FOR RANDOM EFFECTS SELECTION IN LINEAR MIXED MODELS.
Authors: Ahn M. , Zhang H.H. , Lu W. .
Source: Statistica Sinica, 2012-10-01 00:00:00.0; 22(4), p. 1539-1562.
PMID: 23105913
Related Citations

Trajectory analyses in alcohol treatment research.
Authors: Chen J. , Johnson B.A. , Wang X.Q. , O'Quigley J. , Isaac M. , Zhang D. , Liu L. .
Source: Alcoholism, Clinical And Experimental Research, 2012 Aug; 36(8), p. 1442-8.
PMID: 22525000
Related Citations

Corrected-loss estimation for quantile regression with covariate measurement errors.
Authors: Wang H.J. , Stefanski L.A. , Zhu Z. .
Source: Biometrika, 2012 Jun; 99(2), p. 405-421.
PMID: 23843665
Related Citations

Mixed model analysis of censored longitudinal data with flexible random-effects density.
Authors: Vock D.M. , Davidian M. , Tsiatis A.A. , Muir A.J. .
Source: Biostatistics (oxford, England), 2012 Jan; 13(1), p. 61-73.
PMID: 21914727
Related Citations

Estimating Optimal Treatment Regimes from a Classification Perspective.
Authors: Zhang B. , Tsiatis A.A. , Davidian M. , Zhang M. , Laber E. .
Source: Stat, 2012-01-01 00:00:00.0; 1(1), p. 103-114.
PMID: 23645940
Related Citations

A moment-adjusted imputation method for measurement error models.
Authors: Thomas L. , Stefanski L. , Davidian M. .
Source: Biometrics, 2011 Dec; 67(4), p. 1461-70.
PMID: 21385161
Related Citations

Linear or Nonlinear? Automatic Structure Discovery for Partially Linear Models.
Authors: Zhang H.H. , Cheng G. , Liu Y. .
Source: Journal Of The American Statistical Association, 2011-09-01 00:00:00.0; 106(495), p. 1099-1112.
PMID: 22121305
Related Citations

Studying gene and gene-environment effects of uncommon and common variants on continuous traits: a marker-set approach using gene-trait similarity regression.
Authors: Tzeng J.Y. , Zhang D. , Pongpanich M. , Smith C. , McCarthy M.I. , Sale M.M. , Worrall B.B. , Hsu F.C. , Thomas D.C. , Sullivan P.F. .
Source: American Journal Of Human Genetics, 2011-08-12 00:00:00.0; 89(2), p. 277-88.
PMID: 21835306
Related Citations

Discussion of "Connections Between Survey Calibration Estimators and Semiparametric Models for Incomplete Data" by T. Lumley, P.A. Shaw & J.Y. Dai.
Authors: Tsiatis A.A. , Davidian M. .
Source: International Statistical Review = Revue Internationale De Statistique, 2011-08-01 00:00:00.0; 79(2), p. 221-223.
PMID: 21927532
Related Citations

Regression-assisted deconvolution.
Authors: McIntyre J. , Stefanski L.A. .
Source: Statistics In Medicine, 2011-06-30 00:00:00.0; 30(14), p. 1722-34.
EPub date: 2011-06-30 00:00:00.0.
PMID: 21284016
Related Citations

Improved doubly robust estimation when data are monotonely coarsened, with application to longitudinal studies with dropout.
Authors: Tsiatis A.A. , Davidian M. , Cao W. .
Source: Biometrics, 2011 Jun; 67(2), p. 536-45.
PMID: 20731640
Related Citations

FSR Methods for Second-Order Regression Models.
Authors: Crews H.B. , Boos D.D. , Stefanski L.A. .
Source: Computational Statistics & Data Analysis, 2011-06-01 00:00:00.0; 55(6), p. 2026-2037.
PMID: 21479118
Related Citations