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Kaspar Rufibach

Publications and source records attributed to Kaspar Rufibach.

35 records · Page 2Linked to original sources
arXiv2019

Survival analysis for AdVerse events with VarYing follow-up times (SAVVY): Rationale and statistical concept of a meta-analytic study

The assessment of safety is an important aspect of the evaluation of new therapies in clinical trials, with analyses of adverse events being an essential part of this. Standard methods for the analysis of adverse events such as the incidence proportion, i.e. the number of patients with a specific adverse event out of all patients in the treatment groups, do not account for both varying follow-up times and competing risks. Alternative approaches such as the Aalen-Johansen estimator of the cumulative incidence function have been suggested. Theoretical arguments and numerical evaluations support the application of these more advanced methodology, but as yet there is to our knowledge only insufficient empirical evidence whether these methods would lead to different conclusions in safety evaluations. The Survival analysis for AdVerse events with VarYing follow-up times (SAVVY) project strives to close this gap in evidence by conducting a meta-analytical study to assess the impact of the methodology on the conclusion of the safety assessment empirically. Here we present the rationale and statistical concept of the empirical study conducted as part of the SAVVY project. The statistical methods are presented in unified notation and examples of their implementation in R and SAS are provided.

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arXiv2019

Integrating Phase 2 into Phase 3 based on an Intermediate Endpoint While Accounting for a Cure Proportion -- with an Application to the Design of a Clinical Trial in Acute Myeloid Leukemia

For a trial with primary endpoint overall survival for a molecule with curative potential, statistical methods that rely on the proportional hazards assumption may underestimate the power and the time to final analysis. We show how a cure proportion model can be used to get the necessary number of events and appropriate timing via simulation. If Phase 1 results for the new drug are exceptional and/or the medical need in the target population is high, a Phase 3 trial might be initiated after Phase 1. Building in a futility interim analysis into such a pivotal trial may mitigate the uncertainty of moving directly to Phase 3. However, if cure is possible, overall survival might not be mature enough at the interim to support a futility decision. We propose to base this decision on an intermediate endpoint that is sufficiently associated with survival. Planning for such an interim can be interpreted as making a randomized Phase 2 trial a part of the pivotal trial: if stopped at the interim, the trial data would be analyzed and a decision on a subsequent Phase 3 trial would be made. If the trial continues at the interim then the Phase 3 trial is already underway. To select a futility boundary, a mechanistic simulation model that connects the intermediate endpoint and survival is proposed. We illustrate how this approach was used to design a pivotal randomized trial in acute myeloid leukemia, discuss historical data that informed the simulation model, and operational challenges when implementing it.

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arXiv2018

Joint modelling of progression-free and overall survival and computation of correlation measures

In this paper, we derive the joint distribution of progression-free and overall survival as a function of transition probabilities in a multistate model. No assumptions on copulae or latent event times are needed and the model is allowed to be non-Markov. From the joint distribution, statistics of interest can then be computed. As an example, we provide closed formulas and statistical inference for Pearson's correlation coefficient between progression-free and overall survival in a parametric framework. The example is inspired by recent approaches to quantify the dependence between progression-free survival, a common primary outcome in phase III trials in oncology, and overall survival. We complement these approaches by providing methods of statistical inference while at the same time working within a much more parsimonious modelling framework. Our approach is completely general and can be applied to other measures of dependence. We also discuss extensions to nonparametric inference. Our analytical results are illustrated using a large randomized clinical trial in breast cancer.

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arXiv2018

Treatment Effect Quantification for Time-to-event Endpoints -- Estimands, Analysis Strategies, and beyond

A draft addendum to ICH E9 has been released for public consultation in August 2017. The addendum focuses on two topics particularly relevant for randomized confirmatory clinical trials: estimands and sensitivity analyses. The need to amend ICH E9 grew out of the realization of a lack of alignment between the objectives of a clinical trial stated in the protocol and the accompanying quantification of the "treatment effect" reported in a regulatory submission. We embed time-to-event endpoints in the estimand framework, and discuss how the four estimand attributes described in the addendum apply to time-to-event endpoints. We point out that if the proportional hazards assumption is not met, the estimand targeted by the most prevalent methods used to analyze time-to-event endpoints, logrank test and Cox regression, depends on the censoring distribution. We discuss for a large randomized clinical trial how the analyses for the primary and secondary endpoints as well as the sensitivity analyses actually performed in the trial can be seen in the context of the addendum. To the best of our knowledge, this is the first attempt to do so for a trial with a time-to-event endpoint. Questions that remain open with the addendum for time-to-event endpoints and beyond are formulated, and recommendations for planning of future trials are given. We hope that this will provide a contribution to developing a common framework based on the final version of the addendum that can be applied to design, protocols, statistical analysis plans, and clinical study reports in the future.

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arXiv2018

A multistate model for early decision making in oncology

The development of oncology drugs progresses through multiple phases, where after each phase a decision is made about whether to move a molecule forward. Early phase efficacy decisions are often made on the basis of single arm studies based on RECIST tumor response as endpoint. This decision rules are implicitly assuming some form of surrogacy between tumor response and long-term endpoints like progression-free survival (PFS) or overall survival (OS). The surrogacy is most often assessed as weak, but sufficient to allow a rapid decision making as early phase studies lack the survival follow up and number of patients to properly assess PFS or OS. With the emergence of therapies with new mechanisms of action, for which the link between RECIST tumor response and long-term endpoints is either not accessible yet because not enough data is available to perform a meta-regression, or the link is weaker than with classical chemotherapies, tumor response based rules may not be optimal. In this paper, we explore the use of a multistate model for decision making based on single-arm early phase trials. The multistate model allows to account for more information than the simple RECIST response status, namely, the time to get to response, the duration of response, the PFS time and time to death. We propose to base the decision on efficacy on the OS hazard ratio (HR), predicted from a multistate model based on early phase data with limited survival follow-up, combined with historical control data. Using three case studies and simulations, we illustrate the feasibility of the estimation of the OS HR using a multistate model based on limited data from early phase studies. We argue that, in the presence of limited follow up and small sample size, and on assumptions within the multistate model, the OS prediction is acceptable and may lead to better decisions for continuing the development of a drug.

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arXiv2014

Maximum-Likelihood Estimation of a Log-Concave Density based on Censored Data

We consider nonparametric maximum-likelihood estimation of a log-concave density in case of interval-censored, right-censored and binned data. We allow for the possibility of a subprobability density with an additional mass at $+\infty$, which is estimated simultaneously. The existence of the estimator is proved under mild conditions and various theoretical aspects are given, such as certain shape and consistency properties. An EM algorithm is proposed for the approximate computation of the estimator and its performance is illustrated in two examples.

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arXiv2014

SurvRegCensCov: Weibull Regression for a Right-Censored Endpoint with a Censored Covariate

Biomarker data is often subject to limits of quantification and/or limits of detection. Statistically, this corresponds to left- or interval-censoring. To be able to associate a censored time-to-event endpoint to a biomarker covariate, the R package SurvRegCensCov provides software for Weibull regression for a right-censored endpoint, one interval-censored, and an arbitrary number of non-censored covariates. Furthermore, the package provides functions to estimate canonical parameters from censored samples based on several distributional assumptions, and a function to switch between different parametrizations used in R for Weibull regression. We illustrate the new software by applying it to assess Prentice's criteria for surrogacy in data simulated from a randomized clinical registration trial.

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arXiv2012

Asymptotics of the discrete log-concave maximum likelihood estimator and related applications

The assumption of log-concavity is a flexible and appealing nonparametric shape constraint in distribution modelling. In this work, we study the log-concave maximum likelihood estimator (MLE) of a probability mass function (pmf). We show that the MLE is strongly consistent and derive its pointwise asymptotic theory under both the well- and misspecified setting. Our asymptotic results are used to calculate confidence intervals for the true log-concave pmf. Both the MLE and the associated confidence intervals may be easily computed using the R package logcondiscr. We illustrate our theoretical results using recent data from the H1N1 pandemic in Ontario, Canada.

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arXiv2011

A smooth ROC curve estimator based on log-concave density estimates

We introduce a new smooth estimator of the ROC curve based on log-concave density estimates of the constituent distributions. We show that our estimate is asymptotically equivalent to the empirical ROC curve if the underlying densities are in fact log-concave. In addition, we empirically show that our proposed estimator exhibits an efficiency gain for finite sample sizes with respect to the standard empirical estimate in various scenarios and that it is only slightly less efficient, if at all, compared to the fully parametric binormal estimate in case the underlying distributions are normal. The estimator is also quite robust against modest deviations from the log-concavity assumption. We show that bootstrap confidence intervals for the value of the ROC curve at a fixed false positive fraction based on the new estimate are on average shorter compared to the approach by Zhou & Qin (2005), while maintaining coverage probability. Computation of our proposed estimate uses the R package logcondens that implements univariate log-concave density estimation and can be done very efficiently using only one line of code. These obtained results lead us to advocate our estimate for a wide range of scenarios.

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arXiv2011

Selection models with monotone weight functions in meta analysis

Publication bias, the fact that studies identified for inclusion in a meta analysis do not represent all studies on the topic of interest, is commonly recognized as a threat to the validity of the results of a meta analysis. One way to explicitly model publication bias is via selection models or weighted probability distributions. We adopt the nonparametric approach initially introduced by Dear (1992) but impose that the weight function $w$ is monotonely non-increasing as a function of the $p$-value. Since in meta analysis one typically only has few studies or "observations", regularization of the estimation problem seems sensible. In addition, virtually all parametric weight functions proposed so far in the literature are in fact decreasing. We discuss how to estimate a decreasing weight function in the above model and illustrate the new methodology on two well-known examples. The new approach potentially offers more insight in the selection process than other methods and is more flexible than parametric approaches. Some basic properties of the log-likelihood function and computation of a $p$-value quantifying the evidence against the null hypothesis of a constant weight function are indicated. In addition, we provide an approximate selection bias adjusted profile likelihood confidence interval for the treatment effect. The corresponding software and the datasets used to illustrate it are provided as the R package selectMeta. This enables full reproducibility of the results in this paper.

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arXiv2010

An Active Set Algorithm to Estimate Parameters in Generalized Linear Models with Ordered Predictors

In biomedical studies, researchers are often interested in assessing the association between one or more ordinal explanatory variables and an outcome variable, at the same time adjusting for covariates of any type. The outcome variable may be continuous, binary, or represent censored survival times. In the absence of precise knowledge of the response function, using monotonicity constraints on the ordinal variables improves efficiency in estimating parameters, especially when sample sizes are small. An active set algorithm that can efficiently compute such estimators is proposed, and a characterization of the solution is provided. Having an efficient algorithm at hand is especially relevant when applying likelihood ratio tests in restricted generalized linear models, where one needs the value of the likelihood at the restricted maximizer. The algorithm is illustrated on a real life data set from oncology.

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arXiv2009

Least Squares estimation of two ordered monotone regression curves

In this paper, we consider the problem of finding the Least Squares estimators of two isotonic regression curves $g^\circ_1$ and $g^\circ_2$ under the additional constraint that they are ordered; e.g., $g^\circ_1 \le g^\circ_2$. Given two sets of $n$ data points $y_1, ..., y_n$ and $z_1, >...,z_n$ observed at (the same) design points, the estimates of the true curves are obtained by minimizing the weighted Least Squares criterion $L_2(a, b) = \sum_{j=1}^n (y_j - a_j)^2 w_{1,j}+ \sum_{j=1}^n (z_j - b_j)^2 w_{2,j}$ over the class of pairs of vectors $(a, b) \in \mathbb{R}^n \times \mathbb{R}^n $ such that $a_1 \le a_2 \le ...\le a_n $, $b_1 \le b_2 \le ...\le b_n $, and $a_i \le b_i, i=1, ...,n$. The characterization of the estimators is established. To compute these estimators, we use an iterative projected subgradient algorithm, where the projection is performed with a "generalized" pool-adjacent-violaters algorithm (PAVA), a byproduct of this work. Then, we apply the estimation method to real data from mechanical engineering.

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arXiv2009

Limit distribution theory for maximum likelihood estimation of a log-concave density

We find limiting distributions of the nonparametric maximum likelihood estimator (MLE) of a log-concave density, that is, a density of the form $f_0=\expφ_0$ where $φ_0$ is a concave function on $\mathbb{R}$. The pointwise limiting distributions depend on the second and third derivatives at 0 of $H_k$, the "lower invelope" of an integrated Brownian motion process minus a drift term depending on the number of vanishing derivatives of $φ_0=\log f_0$ at the point of interest. We also establish the limiting distribution of the resulting estimator of the mode $M(f_0)$ and establish a new local asymptotic minimax lower bound which shows the optimality of our mode estimator in terms of both rate of convergence and dependence of constants on population values.

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arXiv2009

Maximum likelihood estimation of a log-concave density and its distribution function: Basic properties and uniform consistency

We study nonparametric maximum likelihood estimation of a log-concave probability density and its distribution and hazard function. Some general properties of these estimators are derived from two characterizations. It is shown that the rate of convergence with respect to supremum norm on a compact interval for the density and hazard rate estimator is at least $(\log(n)/n)^{1/3}$ and typically $(\log(n)/n)^{2/5}$, whereas the difference between the empirical and estimated distribution function vanishes with rate $o_{\mathrm{p}}(n^{-1/2})$ under certain regularity assumptions.

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arXiv2007

Marshall's lemma for convex density estimation

Marshall's [Nonparametric Techniques in Statistical Inference (1970) 174--176] lemma is an analytical result which implies $\sqrt{n}$--consistency of the distribution function corresponding to the Grenander [Skand. Aktuarietidskr. 39 (1956) 125--153] estimator of a non-decreasing probability density. The present paper derives analogous results for the setting of convex densities on $[0,\infty)$.

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arXiv2007

Smooth tail index estimation

Both parametric distribution functions appearing in extreme value theory - the generalized extreme value distribution and the generalized Pareto distribution - have log-concave densities if the extreme value index gamma is in [-1,0]. Replacing the order statistics in tail index estimators by their corresponding quantiles from the distribution function that is based on the estimated log-concave density leads to novel smooth quantile and tail index estimators. These new estimators aim at estimating the tail index especially in small samples. Acting as a smoother of the empirical distribution function, the log-concave distribution function estimator reduces estimation variability to a much greater extent than it introduces bias. As a consequence, Monte Carlo simulations demonstrate that the smoothed version of the estimators are well superior to their non-smoothed counterparts, in terms of mean squared error.

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