arXiv subjects

Lorenzo Trippa

Publications and source records attributed to Lorenzo Trippa.

At least 19 recordsLinked to original sources

arXiv2026

Q-approximation of operating characteristics of clinical trial designs

Designing clinical trials requires evaluating multiple operating characteristics (OCs), such as the likelihood of an early stopping decision, the probability of detecting a treatment effect, and the Type I error rate. In most cases, these evaluations are based on computationally intensive Monte Carlo simulations. As the complexity of clinical trials and the use of adaptive designs increase, the computational burden can quickly become prohibitive. We introduce a strategy for rapidly approximating OCs, called the Q-approximation. Our approach is based on quadratic approximations of the log-likelihood and asymptotic arguments. The main idea is to replace simulation of full trial datasets with simulation of the approximate likelihood functions that determine the trial's interim and final decisions. The Q-approximation approach can be applied to any trial design that uses data analysis methods coherent with the likelihood principle, including multistage designs with early stopping, adaptively randomized designs, and designs that leverage external data. We illustrate the approach with several examples and show that it provides an accurate approximation of important OCs while reducing the computation time compared to Monte Carlo simulations. In particular, in our experiments, the standard Monte Carlo approximation of OCs requires 150 to 1,900 times greater computing budget than Q-approximations to achieve comparable levels of accuracy. By enabling fast OC evaluations, Q-approximations can support the broader use of innovative trial designs in both applied trial planning and methodological development.

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arXiv2026

A cautious use of auxiliary outcomes for decision-making in randomized clinical trials

Clinical trials often collect data on multiple outcomes, such as overall survival (OS), progression-free survival (PFS), and response to treatment (RT). In most cases, however, study designs only use primary outcome data for interim and final decision-making. In several disease settings, clinically relevant outcomes, for example OS, become available years after patient enrollment. Moreover, the effects of experimental treatments on OS might be less pronounced compared to auxiliary outcomes such as RT. We develop a Bayesian decision-theoretic framework that uses both primary and auxiliary outcomes for interim and final decision-making. The framework allows investigators to control standard frequentist operating characteristics, such as the type I error rate and can be used with auxiliary outcomes from emerging technologies, such as circulating tumor assays. False positive rates and other frequentist operating characteristics are rigorously controlled without any assumption about the concordance between primary and auxiliary outcomes. We discuss algorithms to implement this decision-theoretic approach and show that incorporating auxiliary information into interim and final decision-making can lead to relevant efficiency gains according to established and interpretable metrics.

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arXiv2025

Leveraging external data in the analysis of randomized controlled trials: a comparative analysis

The use of patient-level information from previous studies, registries, and other external datasets can support the analysis of single-arm and randomized controlled trials to evaluate and test experimental treatments. However, the integration of external data in the analysis of clinical trials can also compromise the scientific validity of the results due to selection bias, study-to-study differences, unmeasured confounding, and other distortion mechanisms. Therefore, leveraging external data in the analysis of a clinical trial requires the use of appropriate methods that can detect, prevent or mitigate the risks of bias and potential distortion mechanisms. We review several methods that allow investigators to leverage external datasets, such as propensity score procedures and random effects modeling. Different methods present distinct trade-offs between risks and efficiencies. We conduct a comparative analysis of statistical methods to leverage external data and analyze randomized controlled trials. Multiple operating characteristics are discussed, such as the control of false positive results, power, and the bias of the treatment effect estimates, across candidate statistical methods. We compare the statistical methods through a broad set of simulation scenarios. We then compare the methods using a collection of datasets with individual patient-level information from several glioblastoma studies in order to provide recommendations for future glioblastoma trials.

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arXiv2025

Leveraging External Data for Testing Experimental Therapies with Biomarker Interactions in Randomized Clinical Trials

In oncology the efficacy of novel therapeutics often differs across patient subgroups, and these variations are difficult to predict during the initial phases of the drug development process. The relation between the power of randomized clinical trials and heterogeneous treatment effects has been discussed by several authors. In particular, false negative results are likely to occur when the treatment effects concentrate in a subpopulation but the study design did not account for potential heterogeneous treatment effects. The use of external data from completed clinical studies and electronic health records has the potential to improve decision-making throughout the development of new therapeutics, from early-stage trials to registration. Here we discuss the use of external data to evaluate experimental treatments with potential heterogeneous treatment effects. We introduce a permutation procedure to test, at the completion of a randomized clinical trial, the null hypothesis that the experimental therapy does not improve the primary outcomes in any subpopulation. The permutation test leverages the available external data to increase power. Also, the procedure controls the false positive rate at the desired $α$-level without restrictive assumptions on the external data, for example, in scenarios with unmeasured confounders, different pre-treatment patient profiles in the trial population compared to the external data, and other discrepancies between the trial and the external data. We illustrate that the permutation test is optimal according to an interpretable criteria and discuss examples based on asymptotic results and simulations, followed by a retrospective analysis of individual patient-level data from a collection of glioblastoma clinical trials.

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arXiv2025

Harmonized Estimation of Subgroup-Specific Treatment Effects in Randomized Trials: The Use of External Control Data

Subgroup analyses of randomized controlled trials (RCTs) constitute an important component of the drug development process in precision medicine. In particular, subgroup analyses of early-stage trials often influence the design and eligibility criteria of subsequent confirmatory trials and ultimately influence which subpopulations will receive the treatment after regulatory approval. However, subgroup analyses are often complicated by small sample sizes, which leads to substantial uncertainty about subgroup-specific treatment effects. We explore the use of external control (EC) data to augment RCT subgroup analyses. We define and discuss harmonized estimators of subpopulation-specific treatment effects that leverage EC data. Our approach can be used to modify any subgroup-specific treatment effect estimates that are obtained by combining RCT and EC data, such as linear regression. We alter these subgroup-specific estimates to make them coherent with a robust estimate of the average effect in the randomized population based only on RCT data. The weighted average of the resulting subgroup-specific harmonized estimates matches the RCT-only estimate of the overall effect in the randomized population. We discuss the proposed harmonized estimators through analytic results and simulations, and investigate standard performance metrics. The method is illustrated with a case study in oncology.

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arXiv2024

Cross-validation Approaches for Multi-study Predictions

We consider prediction in multiple studies with potential differences in the relationships between predictors and outcomes. Our objective is to integrate data from multiple studies to develop prediction models for unseen studies. We propose and investigate two cross-validation approaches applicable to multi-study stacking, an ensemble method that linearly combines study-specific ensemble members to produce generalizable predictions. Among our cross-validation approaches are some that avoid reuse of the same data in both the training and stacking steps, as done in earlier multi-study stacking. We prove that under mild regularity conditions the proposed cross-validation approaches produce stacked prediction functions with oracle properties. We also identify analytically in which scenarios the proposed cross-validation approaches increase prediction accuracy compared to stacking with data reuse. We perform a simulation study to illustrate these results. Finally, we apply our method to predicting mortality from long-term exposure to air pollutants, using collections of datasets.

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arXiv2023

Cross-Study Replicability in Cluster Analysis

In cancer research, clustering techniques are widely used for exploratory analyses and dimensionality reduction, playing a critical role in the identification of novel cancer subtypes, often with direct implications for patient management. As data collected by multiple research groups grows, it is increasingly feasible to investigate the replicability of clustering procedures, that is, their ability to consistently recover biologically meaningful clusters across several datasets. In this paper, we review existing methods to assess replicability of clustering analyses, and discuss a framework for evaluating cross-study clustering replicability, useful when two or more studies are available. These approaches can be applied to any clustering algorithm and can employ different measures of similarity between partitions to quantify replicability, globally (i.e. for the whole sample) as well as locally (i.e. for individual clusters). Using experiments on synthetic and real gene expression data, we illustrate the utility of replicability metrics to evaluate if the same clusters are identified consistently across a collection of datasets.

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arXiv2022

Sensitivity Analyses of Clinical Trial Designs: Selecting Scenarios and Summarizing Operating Characteristics

The use of simulation-based sensitivity analyses is fundamental to evaluate and compare candidate designs for future clinical trials. In this context, sensitivity analyses are especially useful to assess the dependence of important design operating characteristics (OCs) with respect to various unknown parameters (UPs). Typical examples of OCs include the likelihood of detecting treatment effects and the average study duration, which depend on UPs that are not known until after the onset of the clinical study, such as the distributions of the primary outcomes and patient profiles. Two crucial components of sensitivity analyses are (i) the choice of a set of plausible simulation scenarios $\{\boldsymbolθ_1,...,\boldsymbolθ_K\}$ and (ii) the list of OCs of interest. We propose a new approach to choose the set of scenarios for inclusion in design sensitivity analyses. Our approach balances the need for simplicity and interpretability of OCs computed across several scenarios with the need to faithfully summarize -- through simulations -- how the OCs vary across all plausible values of the UPs. Our proposal also supports the selection of the number of simulation scenarios to be included in the final sensitivity analysis report. To achieve these goals, we minimize a loss function $\mathcal{L}(\boldsymbolθ_1,...,\boldsymbolθ_K)$ that formalizes whether a specific set of $K$ sensitivity scenarios $\{\boldsymbolθ_1,...,\boldsymbolθ_K\}$ is adequate to summarize how the OCs of the trial design vary across all plausible values of the UPs. Then, we use optimization techniques to select the best set of simulation scenarios to exemplify the OCs of the trial design.

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arXiv2022

Interpretable Model Summaries Using the Wasserstein Distance

Statistical models often include thousands of parameters. However, large models decrease the investigator's ability to interpret and communicate the estimated parameters. Reducing the dimensionality of the parameter space in the estimation phase is a commonly used approach, but less work has focused on selecting subsets of the parameters for interpreting the estimated model -- especially in settings such as Bayesian inference and model averaging. Importantly, many models do not have straightforward interpretations and create another layer of obfuscation. To solve this gap, we introduce a new method that uses the Wasserstein distance to identify a low-dimensional interpretable model projection. After the estimation of complex models, users can budget how many parameters they wish to interpret and the proposed generates a simplified model of the desired dimension minimizing the distance to the full model. We provide simulation results to illustrate the method and apply it to cancer datasets.

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arXiv2022

Bayesian Multi-Arm De-Intensification Designs

In recent years new cancer treatments improved survival in multiple histologies. Some of these therapeutics, and in particular treatment combinations, are often associated with severe treatment-related adverse events (AEs). It is therefore important to identify alternative de-intensified therapies, for example dose-reduced therapies, with reduced AEs and similar efficacy. We introduce a sequential design for multi-arm de-intensification studies. The design evaluates multiple de-intensified therapies at different dose levels, one at the time, based on modeling of toxicity and efficacy endpoints. We study the utility of the design in oropharynx cancer de-intensification studies. We use a Bayesian nonparametric model for efficacy and toxicity outcomes to define decision rules at interim and final analysis. Interim decisions include early termination of the study due to inferior survival of experimental arms compared to the standard of care (SOC), and transitions from one de-intensified treatment arm to another with a further reduced dose when there is sufficient evidence of non-inferior survival. We evaluate the operating characteristics of the design using simulations and data from recent de-intensification studies in human papillomavirus (HPV)-associated oropharynx cancer.

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arXiv2021

Prediction of Hereditary Cancers Using Neural Networks

Family history is a major risk factor for many types of cancer. Mendelian risk prediction models translate family histories into cancer risk predictions based on knowledge of cancer susceptibility genes. These models are widely used in clinical practice to help identify high-risk individuals. Mendelian models leverage the entire family history, but they rely on many assumptions about cancer susceptibility genes that are either unrealistic or challenging to validate due to low mutation prevalence. Training more flexible models, such as neural networks, on large databases of pedigrees can potentially lead to accuracy gains. In this paper, we develop a framework to apply neural networks to family history data and investigate their ability to learn inherited susceptibility to cancer. While there is an extensive literature on neural networks and their state-of-the-art performance in many tasks, there is little work applying them to family history data. We propose adaptations of fully-connected neural networks and convolutional neural networks to pedigrees. In data simulated under Mendelian inheritance, we demonstrate that our proposed neural network models are able to achieve nearly optimal prediction performance. Moreover, when the observed family history includes misreported cancer diagnoses, neural networks are able to outperform the Mendelian BRCAPRO model embedding the correct inheritance laws. Using a large dataset of over 200,000 family histories, the Risk Service cohort, we train prediction models for future risk of breast cancer. We validate the models using data from the Cancer Genetics Network.

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arXiv2021

Approximating the Operating Characteristics of Bayesian Uncertainty Directed Trial Designs

Bayesian response adaptive clinical trials are currently evaluating experimental therapies for several diseases. Adaptive decisions, such as pre-planned variations of the randomization probabilities, attempt to accelerate the development of new treatments. The design of response adaptive trials, in most cases, requires time consuming simulation studies to describe operating characteristics, such as type I/II error rates, across plausible scenarios. We investigate large sample approximations of pivotal operating characteristics in Bayesian Uncertainty directed trial Designs (BUDs). A BUD trial utilizes an explicit metric u to quantify the information accrued during the study on parameters of interest, for example the treatment effects. The randomization probabilities vary during time to minimize the uncertainty summary u at completion of the study. We provide an asymptotic analysis (i) of the allocation of patients to treatment arms and (ii) of the randomization probabilities. For BUDs with outcome distributions belonging to the natural exponential family with quadratic variance function, we illustrate the asymptotic normality of the number of patients assigned to each arm and of the randomization probabilities. We use these results to approximate relevant operating characteristics such as the power of the BUD. We evaluate the accuracy of the approximations through simulations under several scenarios for binary, time-to-event and continuous outcome models.

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arXiv2020

Combining Breast Cancer Risk Prediction Models

Accurate risk stratification is key to reducing cancer morbidity through targeted screening and preventative interventions. Numerous breast cancer risk prediction models have been developed, but they often give predictions with conflicting clinical implications. Integrating information from different models may improve the accuracy of risk predictions, which would be valuable for both clinicians and patients. BRCAPRO and BCRAT are two widely used models based on largely complementary sets of risk factors. BRCAPRO is a Bayesian model that uses detailed family history information to estimate the probability of carrying a BRCA1/2 mutation, as well as future risk of breast and ovarian cancer, based on mutation prevalence and penetrance (age-specific probability of developing cancer given genotype). BCRAT uses a relative hazard model based on first-degree family history and non-genetic risk factors. We consider two approaches for combining BRCAPRO and BCRAT: 1) modifying the penetrance functions in BRCAPRO using relative hazard estimates from BCRAT, and 2) training an ensemble model that takes as input BRCAPRO and BCRAT predictions. We show that the combination models achieve performance gains over BRCAPRO and BCRAT in simulations and data from the Cancer Genetics Network.

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arXiv2020

Bayesian Combinatorial Multi-Study Factor Analysis

Analyzing multiple studies allows leveraging data from a range of sources and populations, but until recently, there have been limited methodologies to approach the joint unsupervised analysis of multiple high-dimensional studies. A recent method, Bayesian Multi-Study Factor Analysis (BMSFA), identifies latent factors common to all studies, as well as latent factors specific to individual studies. However, BMSFA does not allow for partially shared factors, i.e. latent factors shared by more than one but less than all studies. We extend BMSFA by introducing a new method, Tetris, for Bayesian combinatorial multi-study factor analysis, which identifies latent factors that can be shared by any combination of studies. We model the subsets of studies that share latent factors with an Indian Buffet Process. We test our method with an extensive range of simulations, and showcase its utility not only in dimension reduction but also in covariance estimation. Finally, we apply Tetris to high-dimensional gene expression datasets to identify patterns in breast cancer gene expression, both within and across known classes defined by germline mutations.

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arXiv2020

Integration of Survival Data from Multiple Studies

We introduce a statistical procedure that integrates survival data from multiple biomedical studies, to improve the accuracy of predictions of survival or other events, based on individual clinical and genomic profiles, compared to models developed leveraging only a single study or meta-analytic methods. The method accounts for potential differences in the relation between predictors and outcomes across studies, due to distinct patient populations, treatments and technologies to measure outcomes and biomarkers. These differences are modeled explicitly with study-specific parameters. We use hierarchical regularization to shrink the study-specific parameters towards each other and to borrow information across studies. Shrinkage of the study-specific parameters is controlled by a similarity matrix, which summarizes differences and similarities of the relations between covariates and outcomes across studies. We illustrate the method in a simulation study and using a collection of gene-expression datasets in ovarian cancer. We show that the proposed model increases the accuracy of survival prediction compared to alternative meta-analytic methods.

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arXiv2020

Optimality of testing procedures for survival data

Most statistical tests for treatment effects used in randomized clinical trials with survival outcomes are based on the proportional hazards assumption, which often fails in practice. Data from early exploratory studies may provide evidence of non-proportional hazards which can guide the choice of alternative tests in the design of practice-changing confirmatory trials. We study a test to detect treatment effects in a late-stage trial which accounts for the deviations from proportional hazards suggested by early-stage data. Conditional on early-stage data, among all tests which control the frequentist Type I error rate at a fixed $α$ level, our testing procedure maximizes the Bayesian prediction of the finite-sample power. Hence, the proposed test provides a useful benchmark for other tests commonly used in presence of non-proportional hazards, for example weighted log-rank tests. We illustrate the approach in a simulations based on data from a published cancer immunotherapy phase III trial.

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arXiv2019

Bayesian Mixed Effects Models for Zero-inflated Compositions in Microbiome Data Analysis

Detecting associations between microbial compositions and sample characteristics is one of the most important tasks in microbiome studies. Most of the existing methods apply univariate models to single microbial species separately, with adjustments for multiple hypothesis testing. We propose a Bayesian analysis for a generalized mixed effects linear model tailored to this application. The marginal prior on each microbial composition is a Dirichlet Process, and dependence across compositions is induced through a linear combination of individual covariates, such as disease biomarkers or the subject's age, and latent factors. The latent factors capture residual variability and their dimensionality is learned from the data in a fully Bayesian procedure. The proposed model is tested in data analyses and simulation studies with zero-inflated compositions. In these settings, within each sample, a large proportion of counts per microbial species are equal to zero. In our Bayesian model a priori the probability of compositions with absent microbial species is strictly positive. We propose an efficient algorithm to sample from the posterior and visualizations of model parameters which reveal associations between covariates and microbial compositions. We evaluate the proposed method in simulation studies, and then analyze a microbiome dataset for infants with type 1 diabetes which contains a large proportion of zeros in the sample-specific microbial compositions.

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arXiv2018

Bayesian Uncertainty Directed Trial Designs

Most Bayesian response-adaptive designs unbalance randomization rates towards the most promising arms with the goal of increasing the number of positive treatment outcomes during the study, even though the primary aim of the trial is different. We discuss Bayesian uncertainty directed designs (BUD), a class of Bayesian designs in which the investigator specifies an information measure tailored to the experiment. All decisions during the trial are selected to optimize the available information at the end of the study. The approach can be applied to several designs, ranging from early stage multi-arm trials to biomarker-driven and multi-endpoint studies. We discuss the asymptotic limit of the patient allocation proportion to treatments, and illustrate the finite-sample operating characteristics of BUD designs through examples, including multi-arm trials, biomarker-stratified trials, and trials with multiple co-primary endpoints.

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