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1. Simplifying Causal Mediation Analysis for Time-to-Event Outcomes using Pseudo-Values

Author

Ocampo, Alex, Giudice, Enrico, Häring, Dieter A., Magnusson, Baldur, Lange, Theis, and McCaw, Zachary R.

Subjects
Statistics - Methodology
Abstract

Mediation analysis for survival outcomes is challenging. Most existing methods quantify the treatment effect using the hazard ratio (HR) and attempt to decompose the HR into the direct effect of treatment plus an indirect, or mediated, effect. However, the HR is not expressible as an expectation, which complicates this decomposition, both in terms of estimation and interpretation. Here, we present an alternative approach which leverages pseudo-values to simplify estimation and inference. Pseudo-values take censoring into account during their construction, and once derived, can be modeled in the same way as any continuous outcome. Thus, pseudo-values enable mediation analysis for a survival outcome to fit seamlessly into standard mediation software (e.g. CMAverse in R). Pseudo-values are easy to calculate via a leave-one-observation-out procedure (i.e. jackknifing) and the calculation can be accelerated when the influence function of the estimator is known. Mediation analysis for causal effects defined by survival probabilities, restricted mean survival time, and cumulative incidence functions - in the presence of competing risks - can all be performed within this framework. Extensive simulation studies demonstrate that the method is unbiased across 324 scenarios/estimands and controls the type-I error at the nominal level under the null of no mediation. We illustrate the approach using data from the PARADIGMS clinical trial for the treatment of pediatric multiple sclerosis using fingolimod. In particular, we evaluate whether an imaging biomarker lies on the causal path between treatment and time-to-relapse, which aids in justifying this biomarker as a surrogate outcome. Our approach greatly simplifies mediation analysis for survival data and provides a decomposition of the total effect that is both intuitive and interpretable., Comment: Mediation, Pseudo-Values, Time-to-event, Survival Analysis, Restricted Mean Survival Time, Competing Risks

Published
2024

2. Siponimod: Disentangling disability and relapses in secondary progressive multiple sclerosis

Author

Cree, Bruce AC, Magnusson, Baldur, Rouyrre, Nicolas, Fox, Robert J, Giovannoni, Gavin, Vermersch, Patrick, Bar-Or, Amit, Gold, Ralf, Meier, Daniela Piani, Karlsson, Göril, Tomic, Davorka, Wolf, Christian, Dahlke, Frank, and Kappos, Ludwig

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Multiple Sclerosis, Clinical Trials and Supportive Activities, Neurodegenerative, Neurosciences, Clinical Research, Brain Disorders, Autoimmune Disease, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Azetidines, Benzyl Compounds, Disease Progression, Humans, Multiple Sclerosis, Chronic Progressive, Recurrence, Multiple sclerosis, progressive multiple sclerosis, secondary progressive multiple sclerosis, relapses, progression, siponimod, Neurology & Neurosurgery, Clinical sciences, Biological psychology
Abstract

BackgroundIn multiple sclerosis, impact of treatment on disability progression can be confounded if treatment also reduces relapses.ObjectiveTo distinguish siponimod's direct effects on disability progression from those on relapses in the EXPAND phase 3 trial.MethodsThree estimands, one based on principal stratum and two on hypothetical scenarios (no relapses, or equal relapses in both treatment arms), were defined to determine the extent to which siponimod's effects on 3- and 6-month confirmed disability progression were independent of on-study relapses.ResultsPrincipal stratum analysis estimated that siponimod reduced the risk of 3- and 6-month confirmed disability progression by 14%-20% and 29%-33%, respectively, compared with placebo in non-relapsing patients. In the hypothetical scenarios, risk reductions independent of relapses were 14%-18% and 23% for 3- and 6-month confirmed disability progression, respectively.ConclusionBy controlling the confounding impact of on-study relapses on confirmed disability progression, these statistical approaches provide a methodological framework to assess treatment effects on disability progression in relapsing and non-relapsing patients. The analyses support that siponimod may be useful for treating secondary progressive multiple sclerosis in patients with or without relapses.

Published
2021

3. Tutorial: Effective visual communication for the quantitative scientist

Author

Vandemeulebroecke, Marc, Baillie, Mark, Margolskee, Alison, and Magnusson, Baldur

Subjects
Statistics - Applications
Abstract

Effective visual communication is a core competency for pharmacometricians, statisticians, and more generally any quantitative scientist. It is essential in every step of a quantitative workflow, from scoping to execution and communicating results and conclusions. With this competency, we can better understand data and influence decisions towards appropriate actions. Without it, we can fool ourselves and others and pave the way to wrong conclusions and actions. The goal of this tutorial is to convey this competency. We posit three laws of effective visual communication for the quantitative scientist: have a clear purpose, show the data clearly, and make the message obvious. A concise "Cheat Sheet", available on https://graphicsprinciples.github.io, distills more granular recommendations for everyday practical use. Finally, these laws and recommendations are illustrated in four case studies.

Published
2019

4. Bayesian inference for a principal stratum estimand to assess the treatment effect in a subgroup characterized by post-randomization events

Author

Magnusson, Baldur P., Schmidli, Heinz, Rouyrre, Nicolas, and Scharfstein, Daniel O.

Subjects
Statistics - Applications
Abstract

The treatment effect in a specific subgroup is often of interest in randomized clinical trials. When the subgroup is characterized by the absence of certain post-randomization events, a naive analysis on the subset of patients without these events may be misleading. The principal stratification framework allows one to define an appropriate causal estimand in such settings. Statistical inference for the principal stratum estimand hinges on scientifically justified assumptions, which can be included with Bayesian methods through prior distributions. Our motivating example is a large randomized placebo-controlled trial of siponimod in patients with secondary progressive multiple sclerosis. The primary objective of this trial was to demonstrate the efficacy of siponimod relative to placebo in delaying disability progression for the whole study population. However, the treatment effect in the subgroup of patients who would not relapse during the trial is relevant from both a scientific and regulatory perspective. Assessing this subgroup treatment effect is challenging as there is strong evidence that siponimod reduces relapses. Aligned with the draft regulatory guidance ICH E9(R1), we describe in detail the scientific question of interest, the principal stratum estimand, the corresponding analysis method for binary endpoints and sensitivity analyses., Comment: 16 pages, 2 figures

Published
2018

5. The Safety and Antiviral Activity of BZF961 with or without Ritonavir in Patients Infected with Hepatitis C Virus: A Randomized, Multicenter Trial

Author

Lawitz, Eric, Bidair, Mohamed, Marbury, Thomas, Jones, Christopher T., Barve, Avantika, Magnusson, Baldur, Barkan, David T., Bodendorf, Ursula, Bracken, Kathryn, Canino, Erica, Chen, Darlene, Dabovic, Kristina, Heimbach, Tycho, Ison, Marjorie, Jones, Catherine L., Kovacs, Steven J., Lakshman, Jay P., Li, Bin, Raman, Prakash, Steiner-Swiat, Rachael, Thohan, Sanjeev, Wong, Kelly A., Zhong, Weidong, and Colvin, Richard A.

Published
2018
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8. Spiroindolone KAE609 for Falciparum and Vivax Malaria

Author

White, Nicholas J., Pukrittayakamee, Sasithon, Phyo, Aung Pyae, Rueangweerayut, Ronnatrai, Nosten, François, Jittamala, Podjanee, Jeeyapant, Atthanee, Jain, Jay Prakash, Lefèvre, Gilbert, Li, Ruobing, Magnusson, Baldur, Diagana, Thierry T., and Leong, F. Joel

Published
2014
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9. Cree_EXPAND_CDP_Supplementary_materials_16Sep20 – Supplemental material for Siponimod: Disentangling disability and relapses in secondary progressive multiple sclerosis

Author

Cree, Bruce AC, Magnusson, Baldur, Rouyrre, Nicolas, Fox, Robert J, Giovannoni, Gavin, Vermersch, Patrick, Bar-Or, Amit, Gold, Ralf, Meier, Daniela Piani, Göril Karlsson, Tomic, Davorka, Wolf, Christian, Dahlke, Frank, and Kappos, Ludwig

Subjects
FOS: Clinical medicine, 111702 Aged Health Care, FOS: Health sciences, 110904 Neurology and Neuromuscular Diseases
Abstract

Supplemental material, Cree_EXPAND_CDP_Supplementary_materials_16Sep20 for Siponimod: Disentangling disability and relapses in secondary progressive multiple sclerosis by Bruce AC Cree, Baldur Magnusson, Nicolas Rouyrre, Robert J Fox, Gavin Giovannoni, Patrick Vermersch, Amit Bar-Or, Ralf Gold, Daniela Piani Meier, Göril Karlsson, Davorka Tomic, Christian Wolf, Frank Dahlke and Ludwig Kappos in Multiple Sclerosis Journal

Published
2020
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10. MSO906844 Supplemental Material - Supplemental material for White matter lesion location correlates with disability in relapsing multiple sclerosis

Author

Gaetano, Laura, Magnusson, Baldur, Kindalova, Petya, Tomic, Davorka, Silva, Diego, Altermatt, Anna, Magon, Stefano, Müller-Lenke, Nicole, Ernst-Wilhelm Radue, Leppert, David, Kappos, Ludwig, Wuerfel, Jens, Häring, Dieter A, and Sprenger, Till

Subjects
FOS: Clinical medicine, 110904 Neurology and Neuromuscular Diseases, Neuroscience
Abstract

Supplemental material, MSO906844 Supplemental Material for White matter lesion location correlates with disability in relapsing multiple sclerosis by Laura Gaetano, Baldur Magnusson, Petya Kindalova, Davorka Tomic, Diego Silva, Anna Altermatt, Stefano Magon, Nicole Müller-Lenke, Ernst-Wilhelm Radue, David Leppert, Ludwig Kappos, Jens Wuerfel, Dieter A Häring and Till Sprenger in Multiple Sclerosis Journal—Experimental, Translational and Clinical

Published
2020
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11. Siponimod: Disentangling disability and relapses in secondary progressive multiple sclerosis

Author

Cree, Bruce AC, primary, Magnusson, Baldur, additional, Rouyrre, Nicolas, additional, Fox, Robert J, additional, Giovannoni, Gavin, additional, Vermersch, Patrick, additional, Bar-Or, Amit, additional, Gold, Ralf, additional, Piani Meier, Daniela, additional, Karlsson, Göril, additional, Tomic, Davorka, additional, Wolf, Christian, additional, Dahlke, Frank, additional, and Kappos, Ludwig, additional

Published
2020
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12. White matter lesion location correlates with disability in relapsing multiple sclerosis

Author

Gaetano, Laura, primary, Magnusson, Baldur, additional, Kindalova, Petya, additional, Tomic, Davorka, additional, Silva, Diego, additional, Altermatt, Anna, additional, Magon, Stefano, additional, Müller-Lenke, Nicole, additional, Radue, Ernst-Wilhelm, additional, Leppert, David, additional, Kappos, Ludwig, additional, Wuerfel, Jens, additional, Häring, Dieter A, additional, and Sprenger, Till, additional

Published
2020
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13. How Often Do Safety Signals Occur by Chance in First-in-Human Trials?

Author

Clayton, Gemma L, Schachter, Asher D, Magnusson, Baldur, Li, Yue, and Colin, Laurence

Abstract

Clinicians working on first-in-human clinical studies need to be able to judge whether safety signals observed on an investigational drug were more likely to have occurred by chance or to have been caused by the drug. We retrospectively reviewed 84 Novartis studies including 1,234 healthy volunteers receiving placebo to determine the expected incidence of changes in commonly measured laboratory parameters and vital signs, in the absence of any active agent. We calculated the frequency of random incidence of safety signals, focusing on the liver, cardiovascular system, kidney, and pancreas. Using the liver enzyme alanine aminotransferase (ALT) as an example, we illustrate how a predictive model can be used to determine the probability of a given subject to experience an elevation of ALT above the upper limit of the normal range under placebo, conditional on the characteristics of this subject and the study.

Published
2018
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19. Uncoupling the Impact on Relapses and Disability Progression: Siponimod in Relapsing and Non-relapsing Patients With Secondary Progressive Multiple Sclerosis in the Phase III EXPAND Study (S8.005)

Author

Cree, Bruce, primary, Fox, Robert, additional, Giovannoni, Gavin, additional, Vermersch, Patrick, additional, Bar-Or, Amit, additional, Gold, Ralf, additional, Magnusson, Baldur, additional, Rouyrre, Nicolas, additional, Meier, Daniela Piani, additional, Tomic, Davorka, additional, Karlsson, Goeril, additional, Dahlke, Frank, additional, and Kappos, Ludwig, additional

Published
2018
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21. How can we make better graphs? An initiative to increase the graphical expertise and productivity of quantitative scientists.

Author

Vandemeulebroecke, Marc, Baillie, Mark, Carr, David, Kanitra, Linda, Margolskee, Alison, Wright, Andrew, and Magnusson, Baldur

Subjects
FINGOLIMOD, GRAPHIC methods, EXPERTISE
Abstract

Graphics are at the core of exploring and understanding data, communicating results and conclusions, and supporting decision‐making. Increasing our graphical expertise can significantly strengthen our impact as professional statisticians and quantitative scientists. In this article, we present a concerted effort to improve the way we create graphics at Novartis. We provide our vision and guiding principles, before describing seven work packages in more detail. The actions, principles, and experiences laid out in this paper are applicable generally, also beyond drug development, which is our field of work. The purpose of this article is to share our experiences and help foster the use of good graphs in pharmaceutical statistics and beyond. A Graphics Principles "Cheat Sheet" is available online at https://graphicsprinciples.github.io/. [ABSTRACT FROM AUTHOR]

Published
2019
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24. Antimalarial Activity of KAF156 in Falciparum and Vivax Malaria

Author

White, Nicholas J., primary, Duong, Tran T., additional, Uthaisin, Chirapong, additional, Nosten, François, additional, Phyo, Aung P., additional, Hanboonkunupakarn, Borimas, additional, Pukrittayakamee, Sasithon, additional, Jittamala, Podjanee, additional, Chuthasmit, Kittiphum, additional, Cheung, Ming S., additional, Feng, Yiyan, additional, Li, Ruobing, additional, Magnusson, Baldur, additional, Sultan, Marc, additional, Wieser, Daniela, additional, Xun, Xiaolei, additional, Zhao, Rong, additional, Diagana, Thierry T., additional, Pertel, Peter, additional, and Leong, F. Joel, additional

Published
2016
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26. QAW039 (fevipiprant) improves lung function and control of asthma symptoms in patients with more severe air flow limitation: A proof-of-concept study

Author

Erpenbeck, Veit J., primary, Popov, Todor A., additional, Miller, S. David, additional, Weinstein, Steven F., additional, Spector, Sheldon, additional, Magnusson, Baldur, additional, Osuntokun, Wande, additional, Goldsmith, Paul, additional, Weiss, Markus, additional, and Beier, Jutta, additional

Published
2015
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27. Model averaging for treatment effect estimation in subgroups.

Author

Bornkamp, Björn, Ohlssen, David, Magnusson, Baldur P., and Schmidli, Heinz

Subjects
BAYESIAN analysis, SUBGROUP analysis (Experimental design), CLINICAL trials, MEASUREMENT uncertainty (Statistics), AVERAGING method (Differential equations)
Abstract

In many clinical trials, biological, pharmacological, or clinical information is used to define candidate subgroups of patients that might have a differential treatment effect. Once the trial results are available, interest will focus on subgroups with an increased treatment effect. Estimating a treatment effect for these groups, together with an adequate uncertainty statement is challenging, owing to the resulting 'random high' / selection bias. In this paper, we will investigate Bayesian model averaging to address this problem. The general motivation for the use of model averaging is to realize that subgroup selection can be viewed as model selection, so that methods to deal with model selection uncertainty, such as model averaging, can be used also in this setting. Simulations are used to evaluate the performance of the proposed approach. We illustrate it on an example early-phase clinical trial. [ABSTRACT FROM AUTHOR]

Published
2017
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29. A First-in-Human Randomized, Double-Blind, Placebo-Controlled, Single- and Multiple-Ascending Oral Dose Study of Novel Antimalarial Spiroindolone KAE609 (Cipargamin) To Assess Its Safety, Tolerability, and Pharmacokinetics in Healthy Adult Volunteers

Author

Leong, F. Joel, primary, Li, Ruobing, additional, Jain, Jay Prakash, additional, Lefèvre, Gilbert, additional, Magnusson, Baldur, additional, Diagana, Thierry T., additional, and Pertel, Peter, additional

Published
2014
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32. Estimation of the In VivoMIC of Cipargamin in Uncomplicated Plasmodium falciparumMalaria

Author

Hien, Tran Tinh, White, Nicholas J., Thuy-Nhien, Nguyen Thanh, Hoa, Nhu Thi, Thuan, Phung Duc, Tarning, Joel, Nosten, François, Magnusson, Baldur, Jain, Jay Prakash, and Hamed, Kamal

Abstract

ABSTRACTThe MIC of an antimalarial drug for a particular infection is the drug level associated with a net parasite multiplication rate of one per asexual cycle. To ensure the cure of malaria, the MIC must be exceeded until all parasites have been eliminated. The development of highly sensitive and accurate PCR quantitation of low-density malaria parasitemia enables the prospective pharmacokinetic-pharmacodynamic (PK-PD) characterization of antimalarial drug effects and now allows identification of the in vivoMIC. An adaptive design and a PK-PD modeling approach were used to determine prospectively the MIC of the new antimalarial cipargamin (KAE609) in adults with uncomplicated Plasmodium falciparummalaria in an open-label, dose-ranging phase 2a study. Vietnamese adults with acute P. falciparummalaria were allocated sequentially to treatment with a single 30-mg (n= 6), 20-mg (n= 5), 10-mg (n= 7), or 15-mg (n= 7) dose of cipargamin. Artemisinin-based combination therapy was given after parasite densities had fallen and then risen as cipargamin levels declined below the MIC but before a return of signs or symptoms. The rates of parasite clearance were dose dependent, with near saturation of the effect being seen at an adult dose of 30 mg. The developed PK-PD model accurately predicted the therapeutic responses in 23/25 patients. The predicted median in vivoMIC was 0.126 ng/ml (range, 0.038 to 0.803 ng/ml). Pharmacometric characterization of the relationship between antimalarial drug concentrations and parasite clearance rates following graded subtherapeutic antimalarial drug dosing is safe and provides a rational framework for dose finding in antimalarial drug development. (This study has been registered at ClinicalTrials.gov under identifier NCT01836458.)

Published
2016
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33. Targeted Therapies: Adaptive Sequential Designs For Subgroup Selection In Clinical Trials

Author

Magnusson, Baldur

Subjects
Clinical trial design, Subgroup selection, Multiple comparison procedures
Abstract

A critical part of clinical trials in drug development is the analysis of treatment efficacy in patient subgroups (subpopulations). Due to multiplicity and the small sample sizes involved, this analysis presents substantial statistical challenges and can lead to misleading conclusions. In this thesis, we develop methodology for statistically valid subgroup analysis in a variety of settings. First, we consider a number of trial designs of varying flexibility for the case of one subgroup of interest. Some procedures are novel, while others are adapted from the literature. Included is data-driven consideration of adaptive change of subject eligibility criteria-known as adaptive enrichment-whereby apparently nonresponsive patient populations are not recruited after data has been unblinded for an interim analysis. We conduct an extensive numerical study to investigate design operating characteristics, as well as sensitivity to subgroup prevalence and interim analysis timing. We observe that power gains can be substantial when a treatment is only effective in the subgroup of interest. Following this example, selected procedures are generalized to allow for analysis of an arbitrary number of subgroups. Next, we propose a K -stage group sequential design that can be applied as a confirmatory seamless Phase II/III design. The design is specified through upper and lower spending functions, defined in terms of calendar times. After the first stage, poorly performing subgroups are eliminated and the remaining population is pooled for the duration of the trial. This procedure combines the elimination of non-sensitive subgroups with the definitive assessment of treatment efficacy associated with traditional group sequential designs. Numerical examples show that the procedure has high power to detect subgroup-specific effects, and the use of multiple interim analysis points can lead to substantial sample size savings. We address the challenges of adjusting for selection bias, and protecting the familywise error rate in the strong sense. All designs are presented either in terms of standardized test statistics or the efficient score, making the analysis of normal, binary, or time-to-event data straightforward.

Published
2011

34. Siponimod: Disentangling disability and relapses in secondary progressive multiple sclerosis.

Author

Cree BA, Magnusson B, Rouyrre N, Fox RJ, Giovannoni G, Vermersch P, Bar-Or A, Gold R, Piani Meier D, Karlsson G, Tomic D, Wolf C, Dahlke F, and Kappos L

Subjects
Disease Progression, Humans, Recurrence, Azetidines therapeutic use, Benzyl Compounds therapeutic use, Multiple Sclerosis, Chronic Progressive drug therapy
Abstract

Background: In multiple sclerosis, impact of treatment on disability progression can be confounded if treatment also reduces relapses., Objective: To distinguish siponimod's direct effects on disability progression from those on relapses in the EXPAND phase 3 trial., Methods: Three estimands, one based on principal stratum and two on hypothetical scenarios (no relapses, or equal relapses in both treatment arms), were defined to determine the extent to which siponimod's effects on 3- and 6-month confirmed disability progression were independent of on-study relapses., Results: Principal stratum analysis estimated that siponimod reduced the risk of 3- and 6-month confirmed disability progression by 14%-20% and 29%-33%, respectively, compared with placebo in non-relapsing patients. In the hypothetical scenarios, risk reductions independent of relapses were 14%-18% and 23% for 3- and 6-month confirmed disability progression, respectively., Conclusion: By controlling the confounding impact of on-study relapses on confirmed disability progression, these statistical approaches provide a methodological framework to assess treatment effects on disability progression in relapsing and non-relapsing patients. The analyses support that siponimod may be useful for treating secondary progressive multiple sclerosis in patients with or without relapses.

Published
2021
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