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Minimal sufficient balance--a new strategy to balance baseline covariates and preserve randomness of treatment allocation
In many clinical trials, baseline covariates could affect the primary outcome. Commonly used strategies to balance baseline covariates include stratified constrained randomization and minimization. Stratification is limited to few categorical covariates. Minimization lacks the randomness of treatment allocation. Both apply only to categorical covariates. As a result, serious imbalances could occur in important baseline covariates not included in the randomization algorithm. Furthermore, randomness of treatment allocation could be significantly compromised because of the high proportion of deterministic assignments associat...
Source: Statistical Methods in Medical Research - November 26, 2015 Category: Statistics Authors: Zhao, W., Hill, M. D., Palesch, Y. Tags: Articles Source Type: research

Impact of weighted composite compared to traditional composite endpoints for the design of randomized controlled trials
Composite endpoints are commonly used in cardiovascular clinical trials. When using a composite endpoint a subject is considered to have an event when the first component endpoint has occurred. The use of composite endpoints offers the ability to incorporate several clinically important endpoint events thereby augmenting the event rate and increasing statistical power for a given sample size. One assumption of the composite is that all component events are of equal clinical importance. This assumption is rarely achieved given the diversity of component endpoints included. One means of adjusting for this diversity is to adj...
Source: Statistical Methods in Medical Research - November 26, 2015 Category: Statistics Authors: Bakal, J. A., Westerhout, C. M., Armstrong, P. W. Tags: Articles Source Type: research

Finding differentially expressed genes in high dimensional data: Rank based test statistic via a distance measure
We present a rank-based test statistic for the identification of differentially expressed genes using a distance measure. The proposed test statistic is highly robust against extreme values and does not assume the distribution of parent population. Simulation studies show that the proposed test is more powerful than some of the commonly used methods, such as paired t-test, Wilcoxon signed rank test, and significance analysis of microarray (SAM) under certain non-normal distributions. The asymptotic distribution of the test statistic, and the p-value function are discussed. The application of proposed method is shown using ...
Source: Statistical Methods in Medical Research - November 26, 2015 Category: Statistics Authors: Mathur, S., Sadana, A. Tags: Articles Source Type: research

Multiple comparisons with a control for a latent variable model with ordered categorical responses
Ordered categorical data are frequently encountered in clinical studies. A popular method for comparing the efficacy of treatments is to use logistic regression with the proportional odds assumption. The test statistic is based on the Wilcoxon–Mann–Whitney test. However, the proportional odds assumption may not be appropriate. In such cases, the probability of rejecting the null hypothesis is much inflated even though the treatments have the same mean efficacy. An alternative approach that does not rely on the proportional odds assumption is to conceptualize the responses as manifestations of some underlying co...
Source: Statistical Methods in Medical Research - November 26, 2015 Category: Statistics Authors: Lu, T.-Y., Poon, W.-Y., Cheung, S. H. Tags: Articles Source Type: research

Simpson's paradox - aggregating and partitioning populations in health disparities of lung cancer patients
In this study, we use our original study data of EGFR pathway genetics in African American NSCLC as an example to illustrate that univariate analyses based on aggregation versus partition of data leads to contradictory results, in order to emphasize the importance of controlling statistical confounding. We further investigate analytic approaches in logistic regression for data with separation, as is the case in our example data set, and apply appropriate methods to identify predictors of EGFR mutation. Our simulation shows that with separated or nearly separated data, penalized maximum likelihood (PML) produces estimates w...
Source: Statistical Methods in Medical Research - November 26, 2015 Category: Statistics Authors: Fu, P., Panneerselvam, A., Clifford, B., Dowlati, A., Ma, P., Zeng, G., Halmos, B., Leidner, R. Tags: Articles Source Type: research

Modeling survival data using frailty models
(Source: Statistical Methods in Medical Research)
Source: Statistical Methods in Medical Research - November 26, 2015 Category: Statistics Authors: Hanagal, D. Tags: Articles Source Type: research

Some common errors of experimental design, interpretation and inference in agreement studies
We signal and discuss common methodological errors in agreement studies and the use of kappa indices, as found in publications in the medical and behavioural sciences. Our analysis is based on a proposed statistical model that is in line with the typical models employed in metrology and measurement theory. A first cluster of errors is related to nonrandom sampling, which results in a potentially substantial bias in the estimated agreement. Second, when class prevalences are strongly nonuniform, the use of the kappa index becomes precarious, as its large partial derivatives result in typically large standard errors of the e...
Source: Statistical Methods in Medical Research - November 26, 2015 Category: Statistics Authors: Erdmann, T., De Mast, J., Warrens, M. Tags: Articles Source Type: research

The choice of test in phase II cancer trials assessing continuous tumour shrinkage when complete responses are expected
Traditionally, phase II cancer trials test a binary endpoint formed from a dichotomisation of the continuous change in tumour size. Directly testing the continuous endpoint provides considerable gains in power, although also results in several statistical issues. One such issue is when complete responses, i.e. complete tumour removal, are observed in multiple patients; this is a problem when normality is assumed. Using simulated data and a recently published phase II trial, we investigate how the choice of test affects the operating characteristics of the trial. We propose using parametric tests based on the censored norma...
Source: Statistical Methods in Medical Research - November 26, 2015 Category: Statistics Authors: Wason, J. M., Mander, A. P. Tags: Articles Source Type: research

Vertical modelling: Analysis of competing risks data with missing causes of failure
We propose vertical modelling as a natural approach to the problem of analysis of competing risks data when failure types are missing for some individuals. Under a natural missing-at-random assumption for these missing failure types, we use the observed data likelihood to estimate its parameters and show that the all-cause hazard and the relative hazards appearing in vertical modelling are indeed key quantities of this likelihood. This fact has practical implications in that it suggests vertical modelling as a simple and attractive method of analysis in competing risks with missing causes of failure; all individuals are us...
Source: Statistical Methods in Medical Research - November 26, 2015 Category: Statistics Authors: Nicolaie, M., van Houwelingen, H., Putter, H. Tags: Articles Source Type: research

A two-way enriched clinical trial design: combining advantages of placebo lead-in and randomized withdrawal
A new clinical trial design, designated the two-way enriched design (TED), is introduced, which augments the standard randomized placebo-controlled trial with second-stage enrichment designs in placebo non-responders and drug responders. The trial is run in two stages. In the first stage, patients are randomized between drug and placebo. In the second stage, placebo non-responders are re-randomized between drug and placebo and drug responders are re-randomized between drug and placebo. All first-stage data, and second-stage data from first-stage placebo non-responders and first-stage drug responders, are utilized in the ef...
Source: Statistical Methods in Medical Research - November 26, 2015 Category: Statistics Authors: Ivanova, A., Tamura, R. N. Tags: Articles Source Type: research

Non-parametric estimation of relative risk in survival and associated tests
We extend the Tarone and Ware scheme of weighted log-rank tests to cover the associated weighted Mantel–Haenszel estimators of relative risk. Weighting functions previously employed are critically reviewed. The notion of an average hazard ratio is defined and its connection to the effect size measure P(Y > X) is emphasized. The connection makes estimation of P(Y > X) possible also under censoring. Two members of the extended Tarone–Ware scheme accomplish the estimation of intuitively interpretable average hazard ratios, also under censoring and time-varying relative risk which is achieved by an inverse pr...
Source: Statistical Methods in Medical Research - November 26, 2015 Category: Statistics Authors: Wakounig, S., Heinze, G., Schemper, M. Tags: Articles Source Type: research

Bayesian analysis on meta-analysis of case-control studies accounting for within-study correlation
In retrospective studies, odds ratio is often used as the measure of association. Under independent beta prior assumption, the exact posterior distribution of odds ratio given a single 2 x 2 table has been derived in the literature. However, independence between risks within the same study may be an oversimplified assumption because cases and controls in the same study are likely to share some common factors and thus to be correlated. Furthermore, in a meta-analysis of case–control studies, investigators usually have multiple 2 x 2 tables. In this article, we first extend the published results on a single 2 x 2 table...
Source: Statistical Methods in Medical Research - November 26, 2015 Category: Statistics Authors: Chen, Y., Chu, H., Luo, S., Nie, L., Chen, S. Tags: Articles Source Type: research

Slope estimation for informatively right censored longitudinal data modelling the number of observations using geometric and Poisson distributions: application to renal transplant cohort
In this study, we developed a new likelihood-based approach wherein the likelihood function is integrated over random effects to obtain a marginal likelihood function. Maximum likelihood estimates for the population slope were acquired by direct maximisation of the marginal likelihood function and empirical Bayes estimates for the individual slopes were generated using Gaussian quadrature. The performance of the model was assessed using the geometric and Poisson distributions to model the number of observations for every individual subject. Our model generated valid estimates for the slopes under both distributions with mi...
Source: Statistical Methods in Medical Research - November 26, 2015 Category: Statistics Authors: Jaffa, M. A., Lipsitz, S., Woolson, R. F. Tags: Articles Source Type: research

Optimal designs for epidemiologic longitudinal studies with binary outcomes
This article concerns optimal designs for studies in which the dynamics are modelled as a binary continuous-time Markov process. Either one or both the transition rate parameters in the model are to be estimated with maximum precision from a sequence of observations made at discrete times on a number of subjects. The design questions concern the choice of time interval between observations, the initial state of each subject and the choice between number of subjects versus repeated observations per subject. Sequential designs are considered due to dependence of the designs on the model parameters. The optimal time spacing c...
Source: Statistical Methods in Medical Research - November 26, 2015 Category: Statistics Authors: Mehtälä, J., Auranen, K., Kulathinal, S. Tags: Articles Source Type: research

Linear time-dependent reference intervals where there is measurement error in the time variable - a parametric approach
This article re-examines parametric methods for the calculation of time specific reference intervals where there is measurement error present in the time covariate. Previous published work has commonly been based on the standard ordinary least squares approach, weighted where appropriate. In fact, this is an incorrect method when there are measurement errors present, and in this article, we show that the use of this approach may, in certain cases, lead to referral patterns that may vary with different values of the covariate. Thus, it would not be the case that all patients are treated equally; some subjects would be more ...
Source: Statistical Methods in Medical Research - November 26, 2015 Category: Statistics Authors: Gillard, J. Tags: Articles Source Type: research