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A diverse proteome is present and enzymatically active in metabolite extracts

NATURE COMMUNICATIONS 2024年第1期15卷 5796页

作者： House, Rachel (Rae) J. Soper-Hopper, Molly T. Vincent, Michael P. Ellis, Abigail E. Capan, Colt D. Madaj, Zachary B. Wolfrum, Emily Isaguirre, Christine N. Castello, Carlos D. Johnson, Amy B. Escobar Galvis, Martha L. Williams, Kelsey S. Lee, Hyoungjoo Sheldon, Ryan D. Van Andel Inst Dept Cell Biol Grand Rapids MI USA Van Andel Inst Dept Metab & Nutr Programming Grand Rapids MI USA Van Andel Inst Mass Spectrometry Core Grand Rapids MI 49503 USA Van Andel Inst Bioinformat & Biostat Core Grand Rapids MI USA Van Andel Inst Core Technol & Serv Off Cores Grand Rapids MI USA

Metabolite extraction is the critical first-step in metabolomics experiments, where it is generally regarded to inactivate and remove proteins. Here, arising from efforts to improve extraction conditions for polar metabolomics, we discover a proteomic landscape of over 1000 proteins within metabolite extracts. This is a ubiquitous feature across several common extraction and sample types. By combining post-resuspension stable isotope addition and enzyme inhibitors, we demonstrate in-extract metabolite interconversions due to residual transaminase activity. We extend these findings with untargeted metabolomics where we observe extensive protein-mediated metabolite changes, including in-extract formation of glutamate dipeptide and depletion of total glutathione. Finally, we present a simple extraction workflow that integrates 3 kDa filtration for protein removal as a superior method for polar metabolomics. In this work, we uncover a previously unrecognized, protein-mediated source of observer effects in metabolomics experiments with broad-reaching implications across all research fields using metabolomics and molecular metabolism.

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A variable selection approach for highly correlated predictors in high-dimensional genomic data

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BIOINFORMATICS 2021年第16期37卷 2238-2244页

作者： Zhu, Wencan Levy-Leduc, Celine Ternes, Nils Univ Paris Saclay AgroParisTech UMR MIA Paris INRAE F-75005 Paris France Sanofi R&D Biostat & Programming Dept F-91380 Chilly Mazarin France

Motivation: In genomic studies, identifying biomarkers associated with a variable of interest is a major concern in biomedical research. Regularized approaches are classically used to perform variable selection in high-dimensional linear models. However, these methods can fail in highly correlated settings. Results: We propose a novel variable selection approach called WLasso, taking these correlations into account. It consists in rewriting the initial high-dimensional linear model to remove the correlation between the biomarkers (predictors) and in applying the generalized Lasso criterion. The performance of WLasso is assessed using synthetic data in several scenarios and compared with recent alternative approaches. The results show that when the biomarkers are highly correlated, WLasso outperforms the other approaches in sparse high-dimensional frameworks. The method is also illustrated on publicly available gene expression data in breast cancer.

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A multi-arm two-stage (MATS) design for proof-of-concept and dose optimization in early-phase oncology trials

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CONTEMPORARY CLINICAL TRIALS 2023年第1期132卷 107278-107278页

作者： Jiang, Zhenghao Mi, Gu Lin, Ji Lorenzato, Christelle Ji, Yuan Univ Chicago Dept Stat 5747 South Ellis Ave Chicago IL 60637 USA Sanofi Biostat & Programming 450 Water St Cambridge MA 02141 USA Sanofi R&D Biostat & Programming Vitry sur Seine France Univ Chicago Dept Publ Hlth Sci 5841 South Maryland Ave Chicago IL 60637 USA

The Project Optimus initiative by the FDA's Oncology Center of Excellence is widely viewed as a groundbreaking effort to change the status quo of conventional dose-finding strategies in oncology. Unlike in other therapeutic areas where multiple doses are evaluated thoroughly in dose ranging studies, early-phase oncology dose-finding studies are characterized by the practice of identifying a single dose, such as the maximum tolerated dose (MTD) or the recommended phase 2 dose (RP2D). Following the spirit of Project Optimus, we propose an Multi-Arm Two-Stage (MATS) design for proof-of-concept (PoC) and dose optimization that allows the evaluation of two selected doses from a dose-escalation trial. The design assesses the higher dose first across multiple indications in the first stage, and adaptively enters the second stage for an indication if the higher dose exhibits promising antitumor activities. In the second stage, a randomized comparison between the higher and lower doses is conducted to achieve PoC and dose optimization. A Bayesian hierarchical model governs the statistical inference and decision making by borrowing information across doses, indications, and stages. Our simulation studies show that the proposed MATS design yield desirable performance. An R Shiny application has been developed and made available at https://***/mats/.

关键词： Bayesian hierarchical model Oncology Project Optimus Proof-of-concept

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Seamless phase II/III/IIIb clinical trial designs with different endpoints for different phases

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COMMUNICATIONS IN STATISTICS-THEORY AND METHODS 2020年第22期49卷 5436-5454页

作者： Quan, Hui Luo, Xiaodong Zhou, Tianyue Zhao, Peng-Liang Sanofi Biostat & Programming 55C-335A55 Corp Dr Bridgewater MA 08807 USA

In a seamless phase II/III/IIIb trial, K (K >= 2) doses versus placebo control are evaluated at phase II. Based on phase II results, one dose will be selected for phases III and IIIb. Pre-specified additional numbers of patients will be enrolled into the selected dose and placebo control during phases III and IIIb. Results of the phase III endpoint may be submitted for an early New Drug Application. Final analyses will be conducted for ultimate claims of treatment effects for the selected dose on the phase III and IIIb endpoints. Multiplicity adjustment is performed for the overall type I error rate control.

关键词： Multiplicity adjustment combination test conditional power estimation of treatment effect

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Are self-reported and self-monitored adherence good proxies for reaching relevant plasma concentrations?: Experiences from a study of anti-depressants in healthy volunteers

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CLINICAL TRIALS 2021年第4期18卷 505-510页

作者： Larsen, Klaus Groes Areberg, Johan Astrom, Daniel Oudin H Lundbeck & Co AS Dept Biostat & Programming Copenhagen Denmark H Lundbeck & Co AS Dept PKPD Modelling & Simulat Copenhagen Denmark H Lundbeck & Co AS Dept Value Evidence Analyt Copenhagen Denmark

Background The use of electronic-based devices to measure and to improve adherence of subjects in clinical trials is increasing. AiCure has developed a mobile technology that is claimed to provide visual confirmation of drug ingestion. While there is evidence suggesting that including such self-monitoring device in a study increases adherence, the quality of the data produced by the device may be questionable. Can the mobile technology reliably distinguish whether a subject takes the study drug or not? Methods Adherence was calculated based on exposure, self-reporting and self-monitoring for subjects randomized to an anti-depressant. Levels of adherence and agreement between the three approaches were investigated based on calculation of proportions, two-way tables and receiver operating curves. Results A total of 214 subjects had measured concentrations of study drug at all three time points (end of weeks 3, 4 and 5), along with adherence data to define proportion of days adherent based on self-reporting and the self-monitoring instrument developed by AiCure. Self-reported adherence proportions were higher than self-monitored adherence proportions, although both were high (>90%). Neither self-reported and self-monitored adherence agreed with exposure-based adherence. Conclusion Both self-reported and self-monitored adherence overestimated adherence. Neither the self-reported nor the self-monitored adherence measure reflected subjects' actual adherence. This prompts for cautiousness when interpreting either of them, and it underlines the need for thorough validation of electronic devices and software that claims to measure adherence. The AiCure instrument may not be able to reliably determine whether the subjects swallow the study medication.

关键词： Apps compliance concentration digital monitoring electronic device medication adherence medication compliance

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A model-based clustering via mixture of hierarchical models with covariate adjustment for detecting differentially expressed genes from paired design

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BMC BIOINFORMATICS 2023年第1期24卷 423-423页

作者： Zhang, Yixin Liu, Wei Qiu, Weiliang Univ Sci & Technol China Sch Math Sci Hefei Anhui Peoples R China York Univ Dept Math & Stat Toronto ON Canada Sanofi Dept Biostat & Programming Cambridge MA USA

The causes of many complex human diseases are still largely unknown. Genetics plays an important role in uncovering the molecular mechanisms of complex human diseases. A key step to characterize the genetics of a complex human disease is to unbiasedly identify disease-associated gene transcripts on a whole-genome scale. Confounding factors could cause false positives. Paired design, such as measuring gene expression before and after treatment for the same subject, can reduce the effect of known confounding factors. However, not all known confounding factors can be controlled in a paired/match design. Model-based clustering, such as mixtures of hierarchical models, has been proposed to detect gene transcripts differentially expressed between paired samples. To the best of our knowledge, no model-based gene clustering methods have the capacity to adjust for the effects of covariates yet. In this article, we proposed a novel mixture of hierarchical models with covariate adjustment in identifying differentially expressed transcripts using high-throughput whole-genome data from paired design. Both simulation study and real data analysis show the good performance of the proposed method.

关键词： Curse of dimensionality Confounding EM algorithm RNAseq

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Bayesian modeling of a bivariate toxicity outcome for early phase oncology trials evaluating dose regimens

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STATISTICS IN MEDICINE 2021年第23期40卷 5096-5114页

作者： Gerard, Emma Zohar, Sarah Lorenzato, Christelle Ursino, Moreno Riviere, Marie-Karelle Univ Paris Sorbonne Univ Ctr Rech Cordeliers INSERM 15 Rue Ecole Med F-75006 Paris France INRIA HeKA Paris France Sanofi R&D Oncol Biostat Biostat & Programming Dept Vitry Sur Seine France Sanofi R&D Stat Methodol Grp Biostat & Programming Dept Chilly Mazarin France Univ Paris CHU Robert Debre AP HP Unit Clin EpidemiolINSERMU1123Sorbonne Paris C Paris France CIC EC 1426 Paris France

Most phase I trials in oncology aim to find the maximum tolerated dose (MTD) based on the occurrence of dose limiting toxicities (DLT). Evaluating the schedule of administration in addition to the dose may improve drug tolerance. Moreover, for some molecules, a bivariate toxicity endpoint may be more appropriate than a single endpoint. However, standard dose-finding designs do not account for multiple dose regimens and bivariate toxicity endpoint within the same design. In this context, following a phase I motivating trial, we proposed modeling the first type of DLT, cytokine release syndrome, with the entire dose regimen using pharmacokinetics and pharmacodynamics (PK/PD), whereas the other DLT (DLTo) was modeled with the cumulative dose. We developed three approaches to model the joint distribution of DLT, defining it as a bivariate binary outcome from the two toxicity types, under various assumptions about the correlation between toxicities: an independent model, a copula model and a conditional model. Our Bayesian approaches were developed to be applied at the end of the dose-allocation stage of the trial, once all data, including PK/PD measurements, were available. The approaches were evaluated through an extensive simulation study that showed that they can improve the performance of selecting the true MTD-regimen compared to the recommendation of the dose-allocation method implemented. Our joint approaches can also predict the DLT probabilities of new dose regimens that were not tested in the study and could be investigated in further stages of the trial.

关键词： Bayesian joint modeling bivariate toxicity cumulative probability of toxicity dose regimen early phase oncology pharmacokinetics pharmacodynamics

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Efficacy of Vortioxetine on Anhedonia: Results from a Pooled Analysis of Short-Term Studies in Patients with Major Depressive Disorder

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NEUROPSYCHIATRIC DISEASE AND TREATMENT 2021年 17卷 575-585页

作者： McIntyre, Roger S. Loft, Henrik Christensen, Michael Cronquist Univ Toronto Univ Hlth Network Mood Disorders Psychopharmacol Unit Toronto ON Canada H Lundbeck & Co AS Dept Biostat & Programming Valby Denmark H Lundbeck & Co AS Dept Psychiat Prod Valby Denmark

Purpose: Anhedonia is a core symptom of major depressive disorder (MDD), which has important functional consequences for the patient. This post hoc analysis investigated the relationship between anhedonia and functioning in patients with MDD treated with vortioxetine. Patients and Methods: We conducted a pooled analysis of all 11 short-term, double-blind, randomized, placebo-controlled studies of vortioxetine (fixed dose, 5-20 mg/day) in patients with MDD which included Montgomery-angstrom sberg Depression Rating Scale (MADRS) and Sheehan Disability Scale (SDS) assessments. A short-term, randomized, active-controlled trial of flexible-dose treatment with vortioxetine (10-20 mg/day) versus agomelatine (25-50 mg/day) was also analyzed. Mean changes from baseline to study endpoint in MADRS total, MADRS anhedonia subscale, SDS total, and SDS social-functioning scores were analyzed by a mixed model for repeated measures. The relationship between treatment effects on anhedonia and functioning was investigated using path analysis. Results: A total of 4988 patients with MDD were included in the placebo-controlled studies and 495 in the active-comparator study. Significant dose-dependent improvements in overall depressive symptoms, anhedonia, and measures of functioning were seen in vortioxetine-treated patients compared with those who received placebo or agomelatine. Results of the path analysis for the placebo-controlled studies suggested that the effect on functioning was mostly driven by the effect of treatment on MADRS anhedonia factors. Conclusion: Vortioxetine showed significant short-term efficacy against anhedonia in this large population of patients with MDD. In the placebo-controlled studies, improvements in functioning associated with vortioxetine appeared to be mostly driven by the effect of treatment on MADRS anhedonia factors.

关键词： anhedonia functioning major depressive disorder vortioxetine

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Unified approaches to assessing treatment effect of traditional Chinese medicine based on health profiles

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JOURNAL OF BIOPHARMACEUTICAL STATISTICS 2020年第3期30卷 564-573页

作者： Cheng, Bin Zhang, Bingzhi Chow, Shein-Chung Columbia Univ Dept Biostat New York NY 10032 USA Sanofi Dept Biostat & Programming Bridgewater MA USA Duke Univ Sch Med Dept Biostat & Bioinformat Durham NC USA

Two dissimilarity indices are introduced to measure the disharmony of a human body system by mimicking the population bioequivalence and the individual bioequivalence concepts. Hypotheses for the treatment effect of a traditional Chinese medicine are formulated based on the two indices and then tested under the proposed designs by reverting an approximate confidence upper bound. The proposed methods can also be used when a drug product has multiple components or a trial has multiple endpoints.

关键词： Profile analysis principal component analysis bioequivalence biosimilarity multiple endpoints

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Effectiveness and Safety of Resilient Hyaluronic Acid (RHA) Dermal Fillers for the Correction of Moderate-to-Severe Nasolabial Folds in People of Color: Post Hoc Subgroup Analyses of US Pivotal Clinical Data

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AESTHETIC SURGERY JOURNAL 2024年第4期44卷 412-420页

作者： Taylor, Susan Weinkle, Susan Kaufman-Janette, Joely Gallagher, Conor J. Kooken, Kristie Brown, Jessica Univ Penn Perelman Sch Med Philadelphia PA USA Univ S Florida Dermatol Tampa FL USA Skin Associates South Florida Coral Gables FL USA Revance Therapeut Inc Med Affairs & Sci Innovat Nashville TN USA Revance Therapeut Inc Stat Programming Biostat & Data Management Nashville TN USA Revance Therapeut Inc Med Affairs Nashville TN USA 3400 Civ Ctr Blvd South Tower 7-768 Philadelphia PA 19104 USA

Background People of color (POC) are often underrepresented in clinical studies evaluating the safety and effectiveness of aesthetic products, including hyaluronic acid (HA) fillers, for which there is to date limited clinical data in *** The aim of this study was to assess the safety and effectiveness of a new line of dynamic resilient HA fillers (RHA;Revance, Nashville, TN) for treating moderate-to-severe nasolabial folds (NLFs) in POC vs *** Post hoc subgroup analyses compared the efficacy and safety of POC vs non-POC subjects treated with RHA2, RHA3, or RHA4 for correction of moderate-to-severe NLFs in the pooled per-protocol population (N = 217) in 2 clinical trials. Evaluated population cohorts were classified by Fitzpatrick skin type (FST) (high FST [IV-VI] vs low FST [I-III]) and by subject-reported race (non-White vs White) relative to baseline at 6, 9, 12, and 15 *** POC consistently showed greater improvement in wrinkle severity and higher responder rates compared with non-POC, which reached statistical significance at several measured time points. Global Aesthetic Improvement Scale scores and subject satisfaction ratings were similar for POC and non-POC and remained high throughout the course of the study. Treatment-related adverse event rates were generally lower for high FSTs vs low FSTs, with no reported cases of keloidal *** The RHA line of dynamic fillers is well tolerated and effective for the correction of moderate-to-severe NLFs in POC and can be confidently used in this important and growing patient population.

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