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Raphaël Porcher

Publications and source records attributed to Raphaël Porcher.

13 recordsLinked to original sources

Targeted Active Learning for Preference-Based Treatment Effects on Multivariate Outcomes

Treatment efficacy is traditionally demonstrated on the basis of a single primary outcome. However, clinical decision-making usually requires consideration of multiple outcomes, balancing expected benefits against potential risks. The relative value assigned to these outcomes varies substantially from one patient to another. Given a preference rule over outcome profiles, treatment effects and optimal policies can be defined and estimated. Such a rule is rarely available in practice: it must itself be estimated from pairwise comparisons of outcome profiles, which are costly to collect from clinical experts. We propose an active learning framework that selects which comparisons to query. Standard criteria maximize the information gained on the preference rule itself. We instead target the quantities of interest, and select the query that most reduces uncertainty on the treatment effect and on the optimal policy induced by the learned rule. Under a Gaussian process model of the preference rule, we derive a closed-form approximation of this criterion. On semi-synthetic data built from a Parkinson's disease cohort with 13 clinical outcomes, our criterion achieves lower treatment effect estimation error and lower policy regret than existing criteria at equal query budget.

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Evaluating the influence of treatment-effect heterogeneity on discrimination

Analyzing the heterogeneity of treatment effects is crucial in personalized medicine to identify which patients will benefit from specific treatments. The performance of a conditional average treatment effects model to guide treatment decisions can be assessed in different ways, with an important one being the model's ability to effectively discriminate between individuals who benefit from the treatment and those who do not. While many methods and algorithms have been proposed to develop conditional average treatment effects models and individualized treatment rules, little is known about the discriminative ability that can be achieved according to the population's underlying distribution of treatment effects. In this work, we computed the discrimination that can be achieved under oracle CATE for a panel of 20 distributions with varying average treatment effects and levels of heterogeneity. The assessment included the following discrimination metrics: the c-statistic for benefit, the concentration of benefit, and the population average prescriptive effect (PAPE). Results showed that the three metrics employed in this study did not require the same levels of treatment effect heterogeneity to lead to high discrimination results. Notably, achieving high c-statistic for benefit and PAPE values required greater heterogeneity than obtaining high concentration of benefit values. The three metrics considered behave very differently across the distributions. For instance, the concentration of benefit can indicate perfect discrimination in settings with negligible treatment-effects heterogeneity.

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Choosing Covariate Balancing Methods for Causal Inference: Practical Insights from a Simulation Study

Background: Inverse probability of treatment weighting (IPTW) is used for confounding adjustment in observational studies. Newer weighting methods include energy balancing (EB), kernel optimal matching (KOM), and tailored-loss covariate balancing propensity scores (TLF), but practical guidance remains limited. We evaluate their performance when implemented according to published recommendations. Methods: We conducted Monte Carlo simulations across 36 scenarios varying sample size, treatment prevalence, and a complexity factor increasing confounding and reducing overlap. Data generation used predominantly categorical covariates with some correlation. Average treatment effect and average treatment effect on the treated were estimated using IPTW, EB, KOM, and TLF combined with weighted least squares and, when supported, a doubly robust (DR) estimators. Inference followed published recommendations for each method when feasible, using standard alternatives otherwise. \textsc{PROBITsim} dataset used for illustration. Results: DR reduced sensitivity to the weighting scheme with an outcome regression adjusted for all confounders, despite functional-form misspecification. EB and KOM were most reliable; EB was tuning-free but scale dependent, whereas KOM required kernel and penalty choices. IPTW was variance sensitive when treatment prevalence was far from 50\%. TLF traded lower variance for higher bias, producing an RMSE plateau and sub-nominal confidence interval coverage. \textsc{PROBITsim} results mirrored these patterns. Conclusions: Rather than identifying a best method, our findings highlight failure modes and tuning choices to monitor. When the outcome regression adjusts for all confounders, DR estimation can be dependable across weighting schemes. Incorporating weight-estimation uncertainty into confidence intervals remains a key challenge for newer approaches.

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Evaluating virtual-control-augmented trials for reproducing treatment effect from original RCTs

This study investigates the use of virtual patient data to augment control arms in randomised controlled trials (RCTs). Using data from the IST and IST3 trials, we simulated RCTs in which the recruitment in the control arms would stop after a fraction of the initially planned sample size, and would be completed by virtual patients generated by CTGAN and TVAE, two AI algorithms trained on the recruited control patients. In IST, the absolute risk difference(ARD) on death or dependency at 14 days was -0.012 (SE 0.014). Completing the control arm by CTGAN-generated virtual patients after the recruitment of 10% and 50% of participants, yielded an ARD of 0.004 (SE 0.014) (relative difference 133%) and -0.021 (SE 0.014) (relative difference 76%), respectively. Results were comparable with IST3 or TVAE. This is the first empirical demonstration of the risk of errors and misleading conclusions associated with generating virtual controls solely from trial data.

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Estimating Complier Average Causal Effects with Mixtures of Experts

Treatment non-compliance, where individuals deviate from their assigned experimental conditions, frequently complicates the estimation of causal effects. To address this, we introduce a novel learning framework based on a mixture of experts architecture to estimate the Complier Average Causal Effect (CACE). Our framework provides a flexible alternative to classical instrumental variable methods by relaxing their strict monotonicity and exclusion restriction assumptions. We develop a principled, two-step procedure where each step is optimized with a dedicated Expectation-Maximization (EM) algorithm. Crucially, we provide formal proofs that the model's components are identifiable, ensuring the learning procedure is well-posed. The resulting CACE estimators are proven to be consistent and asymptotically normal. Extensive simulations demonstrate that our method achieves a substantially lower root mean squared error than traditional instrumental variable approaches when their assumptions fail, an advantage that persists even when our own mixture of experts are misspecified. We illustrate the framework's practical utility on data from a large-scale randomized trial.

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Optimal treatment regimes for the net benefit of a treatment

We develop a mathematical framework to define an optimal individualized treatment rule (ITR) within the context of prioritized outcomes in a randomized controlled trial. Our optimality criterion is based on the framework of generalized pairwise comparisons. We propose two approaches for estimating optimal ITRs on a pairwise basis. The first approach is a variant of the k-nearest neighbors algorithm. The second approach is a meta-learning method based on a randomized bagging scheme, which enables the use of any classification algorithm to construct an ITR. We investigate the theoretical properties of these estimation procedures, evaluate their performance through Monte Carlo simulations, and demonstrate their application to clinical trial data.

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G-computation for increasing performances of clinical trials with individual randomization and binary response

In a clinical trial, the random allocation aims to balance prognostic factors between arms, preventing true confounders. However, residual differences due to chance may introduce near-confounders. Adjusting on prognostic factors is therefore recommended, especially because the related increase of the power. In this paper, we hypothesized that G-computation associated with machine learning could be a suitable method for randomized clinical trials even with small sample sizes. It allows for flexible estimation of the outcome model, even when the covariates' relationships with outcomes are complex. Through simulations, penalized regressions (Lasso, Elasticnet) and algorithm-based methods (neural network, support vector machine, super learner) were compared. Penalized regressions reduced variance but may introduce a slight increase in bias. The associated reductions in sample size ranged from 17\% to 54\%. In contrast, algorithm-based methods, while effective for larger and more complex data structures, underestimated the standard deviation, especially with small sample sizes. In conclusion, G-computation with penalized models, particularly Elasticnet with splines when appropriate, represents a relevant approach for increasing the power of RCTs and accounting for potential near-confounders.

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Clinical research and methodology What usage and what hierarchical order for secondary endpoints?

In a randomised clinical trial, when the result of the primary endpoint shows a significant benefit, the secondary endpoints are scrutinised to identify additional effects of the treatment. However, this approach entails a risk of concluding that there is a benefit for one of these endpoints when such benefit does not exist (inflation of type I error risk). There are mainly two methods used to control the risk of drawing erroneous conclusions for secondary endpoints. The first method consists of distributing the risk over several co-primary endpoints, so as to maintain an overall risk of 5%. The second is the hierarchical test procedure, which consists of first establishing a hierarchy of the endpoints, then evaluating each endpoint in succession according to this hierarchy while the endpoints continue to show statistical significance. This simple method makes it possible to show the additional advantages of treatments and to identify the factors that differentiate them.

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Do machine learning methods lead to similar individualized treatment rules? A comparison study on real data

Identifying patients who benefit from a treatment is a key aspect of personalized medicine, which allows the development of individualized treatment rules (ITRs). Many machine learning methods have been proposed to create such rules. However, to what extent the methods lead to similar ITRs, i.e., recommending the same treatment for the same individuals is unclear. In this work, we compared 22 of the most common approaches in two randomized control trials. Two classes of methods can be distinguished. The first class of methods relies on predicting individualized treatment effects from which an ITR is derived by recommending the treatment evaluated to the individuals with a predicted benefit. In the second class, methods directly estimate the ITR without estimating individualized treatment effects. For each trial, the performance of ITRs was assessed by various metrics, and the pairwise agreement between all ITRs was also calculated. Results showed that the ITRs obtained via the different methods generally had considerable disagreements regarding the patients to be treated. A better concordance was found among akin methods. Overall, when evaluating the performance of ITRs in a validation sample, all methods produced ITRs with limited performance, suggesting a high potential for optimism. For non-parametric methods, this optimism was likely due to overfitting. The different methods do not lead to similar ITRs and are therefore not interchangeable. The choice of the method strongly influences for which patients a certain treatment is recommended, drawing some concerns about their practical use.

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A Comprehensive Framework for the Evaluation of Individual Treatment Rules From Observational Data

Individualized treatment rules (ITRs) are deterministic decision rules that recommend treatments to individuals based on their characteristics. Though ubiquitous in medicine, ITRs are hardly ever evaluated in randomized controlled trials. To evaluate ITRs from observational data, we introduce a new probabilistic model and distinguish two situations: i) the situation of a newly developed ITR, where data are from a population where no patient implements the ITR, and ii) the situation of a partially implemented ITR, where data are from a population where the ITR is implemented in some unidentified patients. In the former situation, we propose a procedure to explore the impact of an ITR under various implementation schemes. In the latter situation, on top of the fundamental problem of causal inference, we need to handle an additional latent variable denoting implementation. To evaluate ITRs in this situation, we propose an estimation procedure that relies on an expectation-maximization algorithm. In Monte Carlo simulations our estimators appear unbiased with confidence intervals achieving nominal coverage. We illustrate our approach on the MIMIC-III database, focusing on ITRs for dialysis initiation in patients with acute kidney injury.

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How to improve the quality of comparisons using external control cohorts in single-arm clinical trials?

PURPOSE Providing rapid answers and early acces to patients to innovative treatments without randomized clinical trial (RCT) is growing, with benefit estimated from single-arm trials. This has become common in oncology, impacting the approval pathway of health technology assessment agencies. We aimed to provide some guidance for indirect comparison to external controls to improve the level of evidence following such uncontrolled designs. METHODS We used the illustrative example of blinatumomab, a bispecific antibody for the treatment of B-cell ALL in complete remission (CR) with persistent minimal residual disease (MRD). Its approval relied on a single-arm trial conducted in 86 adults with B-cell ALL in CR, with undetectable MRD after one cycle as the main endpoint. To maximize the validity of indirect comparisons, a 3-step process for incorporating external control data to such single-arm trial data is proposed and detailed, with emphasis on the example. RESULTS The first step includes the definition of estimand, i.e. the treatment effect reflecting the clinical question. The second step relies on the adequate selection of external controls, from previous RCT or real-world data (RWD) obtained from patient cohort, registries, or electronic patient files. The third step consists in chosing the statistical approach targeting the treatment effect of interest, either in the whole population or restricted to the single-arm trial or the external controls, and depending on the available individual-level or aggregrated external data. CONCLUSION Validity of treatment effect derived from indirect comparisons heavily depends on carefull methodological considerations that are included in the proposed 3-step procedure. Because the level of evidence of a well conducted RCT cannot be guaranteed, post-market authorization evaluation is even more important than in standard settings.

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Epidemic Models for COVID-19 during the First Wave from February to May 2020: a Methodological Review

We review epidemiological models for the propagation of the COVID-19 pandemic during the early months of the outbreak: from February to May 2020. The aim is to propose a methodological review that highlights the following characteristics: (i) the epidemic propagation models, (ii) the modeling of intervention strategies, (iii) the models and estimation procedures of the epidemic parameters and (iv) the characteristics of the data used. We finally selected 80 articles from open access databases based on criteria such as the theoretical background, the reproducibility, the incorporation of interventions strategies, etc. It mainly resulted to phenomenological, compartmental and individual-level models. A digital companion including an online sheet, a Kibana interface and a markdown document is proposed. Finally, this work provides an opportunity to witness how the scientific community reacted to this unique situation.

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Wasserstein Random Forests and Applications in Heterogeneous Treatment Effects

We present new insights into causal inference in the context of Heterogeneous Treatment Effects by proposing natural variants of Random Forests to estimate the key conditional distributions. To achieve this, we recast Breiman's original splitting criterion in terms of Wasserstein distances between empirical measures. This reformulation indicates that Random Forests are well adapted to estimate conditional distributions and provides a natural extension of the algorithm to multivariate outputs. Following the philosophy of Breiman's construction, we propose some variants of the splitting rule that are well-suited to the conditional distribution estimation problem. Some preliminary theoretical connections are established along with various numerical experiments, which show how our approach may help to conduct more transparent causal inference in complex situations.

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