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Statistical Methods in Medical Research

Caroline Petit, Adeline Samson, Satoshi Morita, Moreno Ursino, Jérémie Guedj, Vincent Jullien, Emmanuelle Comets, Sarah Zohar
The number of trials conducted and the number of patients per trial are typically small in paediatric clinical studies. This is due to ethical constraints and the complexity of the medical process for treating children. While incorporating prior knowledge from adults may be extremely valuable, this must be done carefully. In this paper, we propose a unified method for designing and analysing dose-finding trials in paediatrics, while bridging information from adults. The dose-range is calculated under three extrapolation options, linear, allometry and maturation adjustment, using adult pharmacokinetic data...
October 4, 2016: Statistical Methods in Medical Research
Patrick Taffé
Bland and Altman's limits of agreement have traditionally been used in clinical research to assess the agreement between different methods of measurement for quantitative variables. However, when the variances of the measurement errors of the two methods are different, Bland and Altman's plot may be misleading; there are settings where the regression line shows an upward or a downward trend but there is no bias or a zero slope and there is a bias. Therefore, the goal of this paper is to clearly illustrate why and when does a bias arise, particularly when heteroscedastic measurement errors are expected, and propose two new plots, the "bias plot" and the "precision plot," to help the investigator visually and clinically appraise the performance of the new method...
October 4, 2016: Statistical Methods in Medical Research
Martin Posch, Florian Klinglmueller, Franz König, Frank Miller
Blinded sample size reassessment is a popular means to control the power in clinical trials if no reliable information on nuisance parameters is available in the planning phase. We investigate how sample size reassessment based on blinded interim data affects the properties of point estimates and confidence intervals for parallel group superiority trials comparing the means of a normal endpoint. We evaluate the properties of two standard reassessment rules that are based on the sample size formula of the z-test, derive the worst case reassessment rule that maximizes the absolute mean bias and obtain an upper bound for the mean bias of the treatment effect estimate...
October 2, 2016: Statistical Methods in Medical Research
Dehui Luo, Xiang Wan, Jiming Liu, Tiejun Tong
The era of big data is coming, and evidence-based medicine is attracting increasing attention to improve decision making in medical practice via integrating evidence from well designed and conducted clinical research. Meta-analysis is a statistical technique widely used in evidence-based medicine for analytically combining the findings from independent clinical trials to provide an overall estimation of a treatment effectiveness. The sample mean and standard deviation are two commonly used statistics in meta-analysis but some trials use the median, the minimum and maximum values, or sometimes the first and third quartiles to report the results...
September 27, 2016: Statistical Methods in Medical Research
Bénédicte Delcoigne, Niels Hagenbuch, Maria Ec Schelin, Agus Salim, Linda S Lindström, Jonas Bergh, Kamila Czene, Marie Reilly
The methods developed for secondary analysis of nested case-control data have been illustrated only in simplified settings in a common cohort and have not found their way into biostatistical practice. This paper demonstrates the feasibility of reusing prior nested case-control data in a realistic setting where a new outcome is available in an overlapping cohort where no new controls were gathered and where all data have been anonymised. Using basic information about the background cohort and sampling criteria, the new cases and prior data are "aligned" to identify the common underlying study base...
September 21, 2016: Statistical Methods in Medical Research
Mohammad Ehsanul Karim, John Petkau, Paul Gustafson, Robert W Platt, Helen Tremlett
In longitudinal studies, if the time-dependent covariates are affected by the past treatment, time-dependent confounding may be present. For a time-to-event response, marginal structural Cox models are frequently used to deal with such confounding. To avoid some of the problems of fitting marginal structural Cox model, the sequential Cox approach has been suggested as an alternative. Although the estimation mechanisms are different, both approaches claim to estimate the causal effect of treatment by appropriately adjusting for time-dependent confounding...
September 21, 2016: Statistical Methods in Medical Research
Douglas J Lorenz, Steven Levy, Somnath Datta
In the marginal analysis of clustered data, where the marginal distribution of interest is that of a typical observation within a typical cluster, analysis by reweighting has been introduced as a useful tool for estimating parameters of these marginal distributions. Such reweighting methods have foundation in within-cluster resampling schemes that marginalize potential informativeness due to cluster size or within-cluster covariate distribution, to which reweighting methods are asymptotically equivalent. In this paper, we introduce a reweighting scheme for the marginal analysis of clustered data that generalizes prior reweighting methods, with a particular application to measuring bivariate correlation in unpaired clustered data, in which observations of two random variables are not naturally paired at the within-cluster level...
September 20, 2016: Statistical Methods in Medical Research
Victoria N Nyaga, Marc Aerts, Marc Arbyn
Procedures combining and summarising direct and indirect evidence from independent studies assessing the diagnostic accuracy of different tests for the same disease are referred to network meta-analysis. Network meta-analysis provides a unified inference framework and uses the data more efficiently. Nonetheless, handling the inherent correlation between sensitivity and specificity continues to be a statistical challenge. We developed an arm-based hierarchical model which expresses the logit transformed sensitivity and specificity as the sum of fixed effects for test, correlated study-effects to model the inherent correlation between sensitivity and specificity and a random error associated with various tests evaluated in a given study...
September 20, 2016: Statistical Methods in Medical Research
Junjiang Zhong, Miin-Jye Wen, Koon Shing Kwong, Siu Hung Cheung
The purpose of a non-inferiority trial is to assert the efficacy of an experimental treatment compared with a reference treatment by showing that the experimental treatment retains a substantial proportion of the efficacy of the reference treatment. Statistical methods have been developed to test multiple experimental treatments in three-arm non-inferiority trials. In this paper, we report the development of procedures that simultaneously test the non-inferiority and the superiority of experimental treatments after the assay sensitivity has been established...
September 19, 2016: Statistical Methods in Medical Research
L Wynants, Y Vergouwe, S Van Huffel, D Timmerman, B Van Calster
Clinical risk prediction models are increasingly being developed and validated on multicenter datasets. In this article, we present a comprehensive framework for the evaluation of the predictive performance of prediction models at the center level and the population level, considering population-averaged predictions, center-specific predictions, and predictions assuming an average random center effect. We demonstrated in a simulation study that calibration slopes do not only deviate from one because of over- or underfitting of patterns in the development dataset, but also as a result of the choice of the model (standard versus mixed effects logistic regression), the type of predictions (marginal versus conditional versus assuming an average random effect), and the level of model validation (center versus population)...
September 19, 2016: Statistical Methods in Medical Research
Valentin Rousson, Marie-Annick Le Pogam, Yves Eggli
Outcome indicators are routinely used to compare hospitals with respect to quality of care. Indicators might be based on observed proportions of adverse events (binary outcomes) or observed averages of e.g. lengths or costs of hospital stays (continuous outcomes). These observed values are compared with expected ones in an average hospital, which might be estimated from a reference sample and should be appropriately adjusted for the case mix of patients. One possibility to achieve a reliable adjustment is to stratify the patients according to their risks, where each patient belongs to one and only one stratum...
September 19, 2016: Statistical Methods in Medical Research
Xiaotian Chen, Yu Cheng, Ellen Frank, David J Kupfer
We aim to close a methodological gap in analyzing durations of successive events that are subject to induced dependent censoring as well as competing-risk censoring. In the Bipolar Disorder Center for Pennsylvanians study, some patients who managed to recover from their symptomatic entry later developed a new depressive or manic episode. It is of great clinical interest to quantify the association between time to recovery and time to recurrence in patients with bipolar disorder. The estimation of the bivariate distribution of the gap times with independent censoring has been well studied...
September 19, 2016: Statistical Methods in Medical Research
Jonathan W Bartlett, Ruth H Keogh
Bayesian approaches for handling covariate measurement error are well established and yet arguably are still relatively little used by researchers. For some this is likely due to unfamiliarity or disagreement with the Bayesian inferential paradigm. For others a contributory factor is the inability of standard statistical packages to perform such Bayesian analyses. In this paper, we first give an overview of the Bayesian approach to handling covariate measurement error, and contrast it with regression calibration, arguably the most commonly adopted approach...
September 19, 2016: Statistical Methods in Medical Research
Soeun Kim, Thomas R Belin, Catherine A Sugar
This paper investigates multiple imputation methods for regression models with interacting continuous and binary predictors when continuous variable may be missing. Usual implementations for parametric multiple imputation assume a multivariate normal structure for the variables, which is not satisfied for a binary variable nor its interaction with a continuous variable. To accommodate interactions, missing covariates are multiply imputed from conditional distribution in a manner consistent with the joint model...
September 19, 2016: Statistical Methods in Medical Research
K A Goldsmith, T Chalder, P D White, M Sharpe, A Pickles
Clinical trials are expensive and time-consuming and so should also be used to study how treatments work, allowing for the evaluation of theoretical treatment models and refinement and improvement of treatments. These treatment processes can be studied using mediation analysis. Randomised treatment makes some of the assumptions of mediation models plausible, but the mediator-outcome relationship could remain subject to bias. In addition, mediation is assumed to be a temporally ordered longitudinal process, but estimation in most mediation studies to date has been cross-sectional and unable to explore this assumption...
September 19, 2016: Statistical Methods in Medical Research
Matthieu Resche-Rigon, Ian R White
In multilevel settings such as individual participant data meta-analysis, a variable is 'systematically missing' if it is wholly missing in some clusters and 'sporadically missing' if it is partly missing in some clusters. Previously proposed methods to impute incomplete multilevel data handle either systematically or sporadically missing data, but frequently both patterns are observed. We describe a new multiple imputation by chained equations (MICE) algorithm for multilevel data with arbitrary patterns of systematically and sporadically missing variables...
September 19, 2016: Statistical Methods in Medical Research
Dena R Howard, Julia M Brown, Susan Todd, Walter M Gregory
Multi-arm clinical trials assessing multiple experimental treatments against a shared control group can offer efficiency advantages over independent trials through assessing an increased number of hypotheses. Published opinion is divided on the requirement for multiple testing adjustment to control the family-wise type-I error rate (FWER). The probability of a false positive error in multi-arm trials compared to equivalent independent trials is affected by the correlation between comparisons due to sharing control data...
September 19, 2016: Statistical Methods in Medical Research
Shaun R Seaman, Rachael A Hughes
Estimating the parameters of a regression model of interest is complicated by missing data on the variables in that model. Multiple imputation is commonly used to handle these missing data. Joint model multiple imputation and full-conditional specification multiple imputation are known to yield imputed data with the same asymptotic distribution when the conditional models of full-conditional specification are compatible with that joint model. We show that this asymptotic equivalence of imputation distributions does not imply that joint model multiple imputation and full-conditional specification multiple imputation will also yield asymptotically equally efficient inference about the parameters of the model of interest, nor that they will be equally robust to misspecification of the joint model...
September 5, 2016: Statistical Methods in Medical Research
Carine Bellera, Cécile Proust-Lima, Lawrence Joseph, Pierre Richaud, Jeremy Taylor, Howard Sandler, James Hanley, Simone Mathoulin-Pélissier
BACKGROUND: Biomarker series can indicate disease progression and predict clinical endpoints. When a treatment is prescribed depending on the biomarker, confounding by indication might be introduced if the treatment modifies the marker profile and risk of failure. OBJECTIVE: Our aim was to highlight the flexibility of a two-stage model fitted within a Bayesian Markov Chain Monte Carlo framework. For this purpose, we monitored the prostate-specific antigens in prostate cancer patients treated with external beam radiation therapy...
September 1, 2016: Statistical Methods in Medical Research
Xing-Rong Liu, Yudi Pawitan, Mark Clements
We describe generalized survival models, where g(S(t|z)), for link function g, survival S, time t, and covariates z, is modeled by a linear predictor in terms of covariate effects and smooth time effects. These models include proportional hazards and proportional odds models, and extend the parametric Royston-Parmar models. Estimation is described for both fully parametric linear predictors and combinations of penalized smoothers and parametric effects. The penalized smoothing parameters can be selected automatically using several information criteria...
September 1, 2016: Statistical Methods in Medical Research
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