Commonly used methods to analyze incomplete longitudinal clinical trial data include complete case analysis (CC) and last observation carried forward (LOCF). However, such methods rest on strong assumptions, including missing completely at random (MCAR) for CC and unchanging profile after dropout for LOCF. Such assumptions are too strong to generally hold. Over the last decades, a number of full longitudinal data analysis methods have become available, such as the linear mixed model for Gaussian outcomes, that are valid under the much weaker missing at random (MAR) assumption. Such a method is useful, even if the scientific question is in terms of a single time point, for example, the last planned measurement occasion, and it is generally consistent with the intention-to-treat principle. The validity of such a method rests on the use of maximum likelihood, under which the missing data mechanism is ignorable as soon as it is MAR. In this paper, we will focus on non-Gaussian outcomes, such as binary, categorical or count data. This setting is less straightforward since there is no unambiguous counterpart to the linear mixed model. We first provide an overview of the various modeling frameworks for non-Gaussian longitudinal data, and subsequently focus on generalized linear mixed-effects models, on the one hand, of which the parameters can be estimated using full likelihood, and on generalized estimating equations, on the other hand, which is a nonlikelihood method and hence requires a modification to be valid under MAR. We briefly comment on the position of models that assume missingness not at random and argue they are most useful to perform sensitivity analysis. Our developments are underscored using data from two studies. While the case studies feature binary outcomes, the methodology applies equally well to other discrete-data settings, hence the qualifier ``discrete'' in the title.
Rheumatoid arthritis clinical trials are strategically designed to collect the disease activity score of each patient over multiple clinical visits, meanwhile a patient may drop out before their intended completion due to various reasons. The dropout terminates the longitudinal data collection on the patients activity score. In the presence of informative dropout, that is, the dropout depends on latent variables from the longitudinal process, simply applying a model to analyze the longitudinal outcomes may lead to biased results because the assumption of random dropout is violated. In this pap…
Statistical research regarding health-related quality of life (HRQoL) is a major challenge to better evaluate the impact of the treatments on their everyday life and to improve patients' care. Among the models that are used for the longitudinal analysis of HRQoL, we focused on the mixed models from the item response theory to analyze directly the raw data from questionnaires. Using a recent classification of generalized linear models for categorical data, we discussed about a conceptual selection of these models for the longitudinal analysis of HRQoL in cancer clinical trials. Through methodol…
Health economic evaluations based on patient-level data collected alongside clinical trials~(e.g. health related quality of life and resource use measures) are an important component of the process which informs resource allocation decisions. Almost inevitably, the analysis is complicated by the fact that some individuals drop out from the study, which causes their data to be unobserved at some time point. Current practice performs the evaluation by handling the missing data at the level of aggregated variables (e.g. QALYs), which are obtained by combining the economic data over the duration o…
Often in Phase 3 clinical trials measuring a long-term time-to-event endpoint, such as overall survival or progression-free survival, investigators also collect repeated measures on biomarkers which may be predictive of the primary endpoint. Although these data may not be leveraged directly to support early stopping decisions, can we make greater use of these data to increase efficiency and improve interim decision making? We present a joint model for longitudinal and time-to-event data and a method which establishes the distribution of successive estimates of parameters in the joint model acr…
In many clinical trials, outcomes of interest include binary-valued endpoints. It is not uncommon that a binary-valued outcome is dichotomized from a continuous outcome at a threshold of clinical interest. To reach the objective, common approaches include (a) fitting the generalized linear mixed model (GLMM) to the dichotomized longitudinal binary outcome and (b) imputation method (MI): imputing the missing values in the continuous outcome, dichotomizing it into a binary outcome, and then fitting the generalized linear model for the "complete" data. We conducted comprehensive simulation studie…
We present a framework for generating multiple imputations for continuous data when the missing data mechanism is unknown. Imputations are generated from more than one imputation model in order to incorporate uncertainty regarding the missing data mechanism. Parameter estimates based on the different imputation models are combined using rules for nested multiple imputation. Through the use of simulation, we investigate the impact of missing data mechanism uncertainty on post-imputation inferences and show that incorporating this uncertainty can increase the coverage of parameter estimates. We …
Missing data is inevitable in longitudinal clinical trials. Conventionally, the missing at random assumption is assumed to handle missingness, which however is unverifiable empirically. Thus, sensitivity analysis is critically important to assess the robustness of the study conclusions against untestable assumptions. Toward this end, regulatory agencies often request using imputation models such as return-to-baseline, control-based, and washout imputation. Multiple imputation is popular in sensitivity analysis; however, it may be inefficient and result in an unsatisfying interval estimation by…
Missing data is unavoidable in longitudinal clinical trials, and outcomes are not always normally distributed. In the presence of outliers or heavy-tailed distributions, the conventional multiple imputation with the mixed model with repeated measures analysis of the average treatment effect (ATE) based on the multivariate normal assumption may produce bias and power loss. Control-based imputation (CBI) is an approach for evaluating the treatment effect under the assumption that participants in both the test and control groups with missing outcome data have a similar outcome profile as those wi…
On a penalised likelihood approach for joint modelling of longitudinal covariates and partly interval-censored data -- an application to the Anti-PD1 brain collaboration trial
When Method Choice Changes Statistical Inference: A Comparison of a Baseline Two-Stage Approach and Bayesian Joint Modeling for Longitudinal and Survival Data in an HIV Clinical Trial
RNA viruses provide prominent examples of measurably evolving populations. In HIV infection, the development of drug resistance is of particular interest, because precise predictions of the outcome of this evolutionary process are a prerequisite for the rational design of antiretroviral treatment protocols. We present a mutagenetic tree hidden Markov model for the analysis of longitudinal clonal sequence data. Using HIV mutation data from clinical trials, we estimate the order and rate of occurrence of seven amino acid changes that are associated with resistance to the reverse transcriptase in…
School of Computing Science, Newcastle University（纽卡斯尔大学计算科学学院）；University Medical Center Utrecht（乌得勒支大学医学中心）；Merck（默克公司）；Bioscience Institute, Newcastle University（纽卡斯尔大学生物科学研究所）；Institut de Recherches Internationales Servier（赛诺菲国际研究所）；GlaxoSmithKline（葛兰素史克公司）；Delft University of Technology（代尔夫特理工大学）；State Research Institute Centre for Innovative Medicine（创新医学国家研究中心）；University of Oulu（奥卢大学）；Versus Arthritis（对抗关节炎组织）
Conventional inclusion criteria used in osteoarthritis clinical trials are not very effective in selecting patients who would benefit from a therapy being tested. Typically majority of selected patients show no or limited disease progression during a trial period. As a consequence, the effect of the tested treatment cannot be observed, and the efforts and resources invested in running the trial are not rewarded. This could be avoided, if selection criteria were more predictive of the future disease progression. In this article, we formulated the patient selection problem as a multi-class class…
Enhancing Longitudinal Clinical Trial Efficiency with Digital Twins and Prognostic Covariate-Adjusted Mixed Models for Repeated Measures (PROCOVA-MMRM)
Palliative medicine is an interdisciplinary specialty focusing on improving quality of life (QOL) for patients with serious illness and their families. Palliative care programs are available or under development at over 80% of large US hospitals (300+ beds). Palliative care clinical trials present unique analytic challenges relative to evaluating the palliative care treatment efficacy which is to improve patients diminishing QOL as disease progresses towards end of life (EOL). A unique feature of palliative care clinical trials is that patients will experience decreasing QOL during the trial d…
Stochastic volatility often implies increasing risks that are difficult to capture given the dynamic nature of real-world applications. We propose using arc length, a mathematical concept, to quantify cumulative variations (the total variability over time) to more fully characterize stochastic volatility. The hazard rate, as defined by the Cox proportional hazards model in survival analysis, is assumed to be impacted by the instantaneous value of a longitudinal variable. However, when cumulative variations pose a significant impact on the hazard, this assumption is questionable. Our proposed B…
The primary outcome of Randomized clinical Trials (RCTs) are typically dichotomous, continuous, multivariate continuous, or time-to-event. However, what if this outcome is unstructured, e.g., a list of variables of mixed types, longitudinal sequences, images, audio recordings, etc. When the outcome is unstructured it is unclear how to assess RCT success and how to compute sample size. We show that kernel methods offer natural extensions to traditional biostatistics methods. We demonstrate our approach with the measurements of computer usage in a cohort of aging participants, some of which will…
Clinical trials in specific indications require the administration of rescue medication in case a patient does not sufficiently respond to investigational treatment. The application of additional treatment on an as needed basis causes problems to the analysis and interpretation of the results of these studies since the effect of the investigational treatment can be confounded by the additional medication. Following-up all patients until study end and capturing all data is not fully addressing the issue. We present an analysis that takes care of the fact that rescue is a study outcome and not a…
In many clinical trials studying neurodegenerative diseases such as Parkinson's disease (PD), multiple longitudinal outcomes are collected to fully explore the multidimensional impairment caused by this disease. If the outcomes deteriorate rapidly, patients may reach a level of functional disability sufficient to initiate levodopa therapy for ameliorating disease symptoms. An accurate prediction of the time to functional disability is helpful for clinicians to monitor patients' disease progression and make informative medical decisions. In this article, we first propose a joint model that cons…
In traditional dose-finding studies, dose-limiting toxicity (DLT) is determined within a fixed time observation window where DLT is often defined as a binary outcome. In the setting of oncology dose-finding trials, often patients in advanced stage of diseases are enrolled. Therefore, disease progression may occur within the DLT observation window leading to treatment discontinuation and rendering the patient unevaluable for DLT assessment. As a result, additional patients have to be enrolled, increasing the sample size. We propose and compare several practical methods for handling disease prog…
Missing data occur in many types of studies and typically complicate the analysis. Multiple imputation, either using joint modelling or the more flexible fully conditional specification approach, are popular and work well in standard settings. In settings involving non-linear associations or interactions, however, incompatibility of the imputation model with the analysis model is an issue often resulting in bias. Similarly, complex outcomes such as longitudinal or survival outcomes cannot be adequately handled by standard implementations. In this paper, we introduce the R package JointAI, whic…
Hepatitis C virus (HCV) coinfection has become one of the most challenging clinical situations to manage in HIV-infected patients. Recently the effect of HCV coinfection on HIV dynamics following initiation of highly active antiretroviral therapy (HAART) has drawn considerable attention. Post-HAART HIV dynamics are commonly studied in short-term clinical trials with frequent data collection design. For example, the elimination process of plasma virus during treatment is closely monitored with daily assessments in viral dynamics studies of AIDS clinical trials. In this article instead we use in…
A pressing challenge in medical research is to identify optimal treatments for individual patients. This is particularly challenging in mental health settings where mean responses are often similar across multiple treatments. For example, the mean longitudinal trajectories for patients treated with an active drug and placebo may be very similar but different treatments may exhibit distinctly different individual trajectory shapes. Most precision medicine approaches using longitudinal data often ignore information from the longitudinal data structure. This paper investigates a powerful precisio…
Mixed model repeated measures (MMRM) is the most common analysis approach used in clinical trials for Alzheimer's disease and other progressive diseases measured with continuous outcomes measured over time. The model treats time as a categorical variable, which allows an unconstrained estimate of the mean for each study visit in each randomized group. Categorizing time in this way can be problematic when assessments occur off-schedule, as including off-schedule visits can induce bias, and excluding them ignores valuable information and violates the intention to treat principle. This problem ha…
Parkinson's disease (PD) is a chronic, degenerative neurological disorder. PD cannot be prevented, slowed or cured as of today but highly effective symptomatic treatments are available. We consider relevant estimands and treatment effect estimators for randomized trials of a novel treatment which aims to slow down disease progression versus placebo in early, untreated PD. A commonly used endpoint in PD trials is the MDS-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), which is longitudinally assessed at scheduled visits. The most important intercurrent events (ICEs) which affect the inter…
Data collected in clinical trials are often composed of multiple types of variables. For example, laboratory measurements and vital signs are longitudinal data of continuous or categorical variables, adverse events may be recurrent events, and death is a time-to-event variable. Missing data due to patients' discontinuation from the study or as a result of handling intercurrent events using a hypothetical strategy almost always occur during any clinical trial. Imputing these data with mixed types of variables simultaneously is a challenge that has not been studied extensively. In this article, …
We develop flexible multi-parameter regression survival models for interval censored survival data arising in longitudinal prospective studies and longitudinal randomised controlled clinical trials. A multi-parameter Weibull regression survival model, which is wholly parametric, and has non-proportional hazards, is the main focus of the paper. We describe the basic model, develop the interval-censored likelihood and extend the model to include gamma frailty and a dispersion model. We evaluate the models by means of a simulation study and a detailed re-analysis of data from the Signal Tandmobie…
Most analyses of randomised trials with incomplete outcomes make untestable assumptions and should therefore be subjected to sensitivity analyses. However, methods for sensitivity analyses are not widely used. We propose a mean score approach for exploring global sensitivity to departures from missing at random or other assumptions about incomplete outcome data in a randomised trial. We assume a single outcome analysed under a generalised linear model. One or more sensitivity parameters, specified by the user, measure the degree of departure from missing at random in a pattern mixture model. A…
Longitudinal data are common in clinical trials and observational studies, where missing outcomes due to dropouts are always encountered. Under such context with the assumption of missing at random, the weighted generalized estimating equations (WGEE) approach is widely adopted for marginal analysis. Model selection on marginal mean regression is a crucial aspect of data analysis, and identifying an appropriate correlation structure for model fitting may also be of interest and importance. However, the existing information criteria for model selection in WGEE have limitations, such as separate…
In this article, we propose a new method for analyzing longitudinal data which contain responses that are missing at random. This method consists in solving the generalized estimating equation (GEE) of Liang and Zeger (1986) in which the incomplete responses are replaced by values adjusted using the inverse probability weights proposed in Yi, Ma and Carroll (2012). We show that the root estimator is consistent and asymptotically normal, essentially under the some conditions on the marginal distribution and the surrogate correlation matrix as those presented in Xie and Yang (2003) in the case o…
We develop inference procedures for longitudinal data where some of the measurements are censored by fixed constants. We consider a semi-parametric quantile regression model that makes no distributional assumptions. Our research is motivated by the lack of proper inference procedures for data from biomedical studies where measurements are censored due to a fixed quantification limit. In such studies the focus is often on testing hypotheses about treatment equality. To this end, we propose a rank score test for large sample inference on a subset of the covariates. We demonstrate the importance …
