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Sharma R, Gulati A, Chopra K. Era of surrogate endpoints and accelerated approvals: a comprehensive review on applicability, uncertainties, and challenges from regulatory, payer, and patient perspectives. Eur J Clin Pharmacol 2025; 81:605-623. [PMID: 40080138 DOI: 10.1007/s00228-025-03822-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Accepted: 03/03/2025] [Indexed: 03/15/2025]
Abstract
PURPOSE The regulatory landscape in rare diseases and oncology has evolved to address unmet medical needs by implementing expedited approval pathways. The US FDA's Accelerated Approval and the EMA's Conditional Marketing Authorization facilitate earlier patient access to therapies through reliance on surrogate endpoints derived from early-phase clinical trials. The review aims to provide a comprehensive review of the role and utilization of surrogate endpoints in accelerated drug approvals, highlighting their strengths, limitations, and the varying perspectives of stakeholders on their validity and utility. METHODS This article reviews existing literature and regulatory guidelines to assess the effectiveness and challenges associated with surrogate endpoints in expedited approval pathways. It also examines the post-approval commitment adherence required by regulatory bodies, exploring discrepancies among stakeholder perspectives. RESULTS Findings indicate that while surrogate endpoints enable faster market access, uncertainties remain regarding post-approval commitments and their consistency. Differences in stakeholder opinions also persist, reflecting varying levels of confidence in the validity and applicability of surrogate endpoints. CONCLUSION Surrogate endpoints play a crucial role in accelerating drug approvals in areas with high unmet needs, yet challenges around post-approval commitments and stakeholder acceptance suggest the need for enhanced regulatory clarity and ongoing assessment of surrogate endpoint validity.
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Affiliation(s)
- Rohini Sharma
- University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, 160014, India.
| | - Anamika Gulati
- Centre for Studies in Science Policy, School of Social Sciences, Jawaharlal Nehru University, New Delhi, India
| | - Kanwaljit Chopra
- University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, 160014, India.
- Pharmacology Research Laboratory, UGC Centre of Advanced Studies, University Institute of Pharmaceutical Sciences (UIPS), Panjab University, Chandigarh, 160014, India.
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2
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Couturier A, Wykoff CC, Lupidi M, Udaondo P, Peto T, Pintard PJ. Anatomic biomarkers as potential endpoints in diabetic macular edema: A systematic literature review with identification of macular volume as a key surrogate for visual acuity. Surv Ophthalmol 2025:S0039-6257(25)00069-4. [PMID: 40318769 DOI: 10.1016/j.survophthal.2025.04.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 04/25/2025] [Accepted: 04/28/2025] [Indexed: 05/07/2025]
Abstract
Optimization of diabetic macular edema (DME) treatment pathways can aid in the efficient introduction of new therapies that provide value to patients and healthcare systems. We performed a systematic literature review and multicorrelation analysis to identify and evaluate anatomic biomarkers as potential surrogate endpoints (SEs) for visual acuity (VA) in patients with DME. We performed EMBASE and MEDLINE searches to identify studies reporting on 4 priority biomarkers previously identified by clinical experts: hyperreflective foci, intraretinal cyst, macular volume (MV), and subretinal fluid. Endpoint and treatment effect correlation analyses were performed to establish correlation coefficients between MV and VA using Pearson's correlation. A total of 105 studies reported change from baseline data for VA, and at least 1 biomarker, with MV investigated most often (n = 70 studies). Data extracted from 55 studies focusing on the 6-mm zone for MV were used in statistical analyses. A moderate correlation was observed between MV and VA at the endpoint level (r = 0.58; p < 0.01); however, a corresponding treatment effect was not found (r = 0.32; p = 0.19). Our findings suggest MV's potential as an SE for VA in future clinical practice; however, the lack of a significant treatment effect warrants that these findings be interpreted cautiously. Further evidence and improvements in reporting the methods for collecting biomarker data are needed. Analysis of outliers and subanalyses by other optical coherence tomography measures could establish the most meaningful MV values correlating with VA.
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Affiliation(s)
- Aude Couturier
- Université Paris Cité, Service d'Ophtalmologie, Hôpital Lariboisière, APHP, Paris F-75475, France
| | - Charles C Wykoff
- Retina Consultants of Texas, Houston, TX, USA; Blanton Eye Institute, Houston Methodist Hospital & Weill Cornell Medical College, Houston, TX, USA
| | - Marco Lupidi
- Eye Clinic, Department of Experimental and Clinical Medicine, Polytechnic University of Marche, Ancona 60131, Italy; Fondazione per la Macula Onlus, Dipartimento di Neuroscienze, Riabilitazione, Oftalmologia, Genetica e Scienze Materno-Infantili (DINOGMI), University Eye Clinic, Genova 16132, Italy
| | - Patricia Udaondo
- Hospital Universitari i Politècnic La Fe, Avinguda Fernando Abril Martorell, No. 106, Valencia, Spain; Aiken Clinic, Aiken Fundation, Valencia, Spain
| | - Tunde Peto
- Centre for Public Health, Queen's University, Belfast, Northern Ireland, UK
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3
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Raulinaite K, Zelvyte R, Skemiene K, Monkeviciene I. Treatment tactic of canine cranial cruciate ligament rupture management: A 28-day comparative analysis of ACP and NSAID induced effects on the serum MMP-3 levels and clinical outcomes. VET MED-CZECH 2025; 70:124-133. [PMID: 40406605 PMCID: PMC12093463 DOI: 10.17221/39/2024-vetmed] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Accepted: 02/23/2025] [Indexed: 05/26/2025] Open
Abstract
Cranial cruciate ligament rupture (CrCLR) is a common stifle joint pathology among dogs, leading to osteoarthritis and painfulness. Non-surgical treatment options often represent the usage of non-steroidal anti-inflammatory drugs for 14 days (NSAIDs), but autologous conditioned plasma (ACP) shows promising results in managing various orthopaedic conditions, decreasing inflammation, and improving the clinical outcome in dogs. This study aimed to determine the differences in MMP-3 serum levels and the clinical outcomes between differently treated cranial cruciate rupture cases. For this purpose, we used two different treatment methods for managing canine cranial cruciate ligament rupture (minimally invasive ACP injection or oral NSAIDs), and evaluated the clinical outcomes, indicating the quality of life, and the MMP-3 serum levels over a period of 28 days. The findings of this investigation indicate that ACP has better efficacy than two weeks of NSAIDs in inflammation reduction, clinical outcome improvement, and the allowance of a longer duration of activity after 28 days.
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Affiliation(s)
- Kristina Raulinaite
- Department of Anatomy and Physiology, Faculty of Veterinary, Veterinary Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Rasa Zelvyte
- Department of Anatomy and Physiology, Faculty of Veterinary, Veterinary Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Kristina Skemiene
- Laboratory of Biochemistry, Neuroscience Institute, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Ingrida Monkeviciene
- Department of Anatomy and Physiology, Faculty of Veterinary, Veterinary Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania
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4
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Ong F, Molenberghs G, Callegaro A, Van Der Elst W, Verbeke G, Stijven F, Keilegom IV, Abad AA. Evaluating Hemagglutination Inhibition Antibody Titers as a Correlate of Protection for Influenza: A Sensitivity Analysis Based on Information Theory and Causal Inference. J Glob Infect Dis 2025; 17:17-23. [PMID: 40290204 PMCID: PMC12021349 DOI: 10.4103/jgid.jgid_89_24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2024] [Revised: 07/25/2024] [Accepted: 08/02/2024] [Indexed: 04/30/2025] Open
Abstract
Introduction Identifying hemagglutination inhibition (HI) antibody titers as a key immune correlate of protection (CoP) is crucial for developing, licensing, and monitoring the ongoing effectiveness of new influenza vaccines. Using a new statistical methodology, we explored the link between an inactivated quadrivalent influenza vaccine's impact on HI antibody titers and its effectiveness against A/H1N1-associated influenza illness. Methods We utilized data from a phase 3, observer-blind, randomized, controlled trial in children aged 6-35 months to assess HI antibody titers as an immune CoP. The assessment used a statistical method developed within a causal inference framework and a new information-theoretic metric of surrogacy, the so-called individual causal association (ICA). Results The 75% and 85% uncertainty intervals of the ICA are 0.5511-0.8282 and 0.3632-0.8684, respectively, indicating a substantial reduction in the uncertainty about the vaccine's effect on the absence of infection when its impact on the HI antibody titers is known. Conclusions The evaluation yielded evidence supporting the validity of HI antibody titers as a CoP for influenza infection.
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Affiliation(s)
- Fenny Ong
- I-BioStat, Universiteit Hasselt, Diepenbeek, Belgium
| | - Geert Molenberghs
- I-BioStat, Universiteit Hasselt, Diepenbeek, Belgium
- I-BioStat, KU Leuven, Leuven, Belgium
| | | | - Wim Van Der Elst
- The Janssen Pharmaceutical Companies of Johnson and Johnson, Beerse, Belgium
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Higgins KM, Levin G, Busch R. Considerations for open-label randomized clinical trials: Design, conduct, and analysis. Clin Trials 2024; 21:681-688. [PMID: 38618711 DOI: 10.1177/17407745241244788] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/16/2024]
Abstract
Randomization and blinding are regarded as the most important tools to help reduce bias in clinical trial designs. Randomization is used to help guarantee that treatment arms differ systematically only by treatment assignment at baseline, and blinding is used to ensure that differences in endpoint evaluation and clinical decision-making during the trial arise only from the treatment received and not, for example, the expectation or desires of the people involved. However, given that there are times when it is not feasible or ethical to conduct fully blinded trials, we discuss what can be done to improve a trial, including conducting the trial as if it were a fully blinded trial and maintaining confidentiality of ongoing study results. In this article, we review how best to design, conduct, and analyze open-label trials to ensure the highest level of study integrity and the reliability of the study conclusions.
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Affiliation(s)
- Karen M Higgins
- Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA
| | - Gregory Levin
- Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA
| | - Robert Busch
- Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA
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6
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Pathak A, Jain NK, Jain K. Dendrimer-mediated targeting of angiogenic biomarkers: therapeutic intervention against cancer. Expert Opin Drug Deliv 2024; 21:1235-1250. [PMID: 39161976 DOI: 10.1080/17425247.2024.2394631] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Accepted: 08/16/2024] [Indexed: 08/21/2024]
Abstract
INTRODUCTION Development of novel vascular networks is a fundamental requirement for tumor growth and progression. In the last decade, biomarkers and underlying molecular pathways of angiogenesis have been intensely investigated to disrupt the initiation and progression of tumor angiogenesis. However, the clinical applications of anti-angiogenic agents are constrained due to toxic side effects, acquired drug resistance, and unavailability of validated biomarkers. AREA COVERED This review discusses the development of dendrimeric nanocarriers that could be a promising domain to explore for the eradication of current challenges associated with angiogenesis-based cancer therapy. Novel drug-delivery approaches with subtle readouts and better understanding of molecular mechanisms have revealed that dendrimers comprise innate anti-angiogenic activity and incorporation of anti-angiogenic agents or gene-silencing RNA could lead to synergistic anti-angiogenic and anticancer effects with reduced side effects. EXPERT OPINION Dendrimer-mediated targeting of angiogenic biomarkers has efficiently led to the vascular normalization, and rational linking of dendrimers with anti-angiogenic agent or siRNA or both might be a potential area to eradicate the current challenges of angiogenesis-based cancer therapy. However, drawbacks associated with the dendrimers-mediated targeting of angiogenic biomarkers, such as poor stability or small expression of these biomarkers on the normal cells, limit their application at market scale.
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Affiliation(s)
- Anchal Pathak
- Drug Delivery and Nanomedicine Research Laboratory, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER) - Raebareli, Lucknow, India
| | - Narendra Kumar Jain
- Department of Pharmaceutical Sciences, Dr. H. S. Gour Central University, Sagar, India
| | - Keerti Jain
- Drug Delivery and Nanomedicine Research Laboratory, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER) - Raebareli, Lucknow, India
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Guo X, Bourgeois FT, Cai T. Quantifying proportion of treatment effect by surrogate endpoint under heterogeneity. Stat Methods Med Res 2024; 33:1152-1162. [PMID: 38717356 DOI: 10.1177/09622802241247719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/27/2024]
Abstract
When the primary endpoints in randomized clinical trials require long term follow-up or are costly to measure, it is often desirable to assess treatment effects on surrogate instead of clinical endpoints. Prior to adopting a surrogate endpoint for such purposes, the extent of its surrogacy on the primary endpoint must be assessed. There is a rich statistical literature on assessing surrogacy in the overall population, much of which is based on quantifying the proportion of treatment effect on the primary endpoint that is explained by the treatment effect on the surrogate endpoint. However, the surrogacy of an endpoint may vary across different patient subgroups according to baseline demographic characteristics, and limited methods are currently available to assess overall surrogacy in the presence of potential surrogacy heterogeneity. In this paper, we propose methods that incorporate covariates for baseline information, such as age, to improve overall surrogacy assessment. We use flexible semi-non-parametric modeling strategies to adjust for covariate effects and derive a robust estimate for the proportion of treatment effect of the covariate-adjusted surrogate endpoint. Simulation results suggest that the adjusted surrogate endpoint has greater proportion of treatment effect compared to the unadjusted surrogate endpoint. We apply the proposed method to data from a clinical trial of infliximab and assess the adequacy of the surrogate endpoint in the presence of age heterogeneity.
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Affiliation(s)
- Xinzhou Guo
- Department of Mathematics, Hong Kong University of Science and Technology, Hong Kong, China
- Harvard-MIT Center for Regulatory Science, Harvard Medical School, Boston, MA, USA
| | - Florence T Bourgeois
- Harvard-MIT Center for Regulatory Science, Harvard Medical School, Boston, MA, USA
- Pediatric Therapeutics and Regulatory Science Initiative, Computational Health Informatics Program (CHIP), Boston Children's Hospital, Boston, MA, USA
| | - Tianxi Cai
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA
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8
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Christensen R, Ciani O, Manyara AM, Taylor RS. Low-density lipoprotein cholesterol is not a successful surrogate endpoint: author's reply. J Clin Epidemiol 2024; 171:111389. [PMID: 38723781 DOI: 10.1016/j.jclinepi.2024.111389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Accepted: 05/02/2024] [Indexed: 05/31/2024]
Affiliation(s)
- Robin Christensen
- Section for Biostatistics and Evidence-Based Research, the Parker Institute, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark; Research Unit of Rheumatology, Department of Clinical Research, University of Southern Denmark, Odense University Hospital, Denmark.
| | - Oriana Ciani
- Centre for Research on Health and Social Care Management, SDA Bocconi, Milan, Italy
| | - Anthony M Manyara
- School of Health and Wellbeing, University of Glasgow, Glasgow, UK; Global Health and Ageing Research Unit, Bristol Medical School, University of Bristol, Bristol, UK
| | - Rod S Taylor
- MRC/CSO Social and Public Health Sciences Unit, Glasgow, Scotland, UK; Robertson Centre for Biostatistics, School of Health and Well Being, University of Glasgow, Glasgow, UK
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9
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Zeng S, Qing Q, Xu W, Yu S, Zheng M, Tan H, Peng J, Huang J. Personalized anesthesia and precision medicine: a comprehensive review of genetic factors, artificial intelligence, and patient-specific factors. Front Med (Lausanne) 2024; 11:1365524. [PMID: 38784235 PMCID: PMC11111965 DOI: 10.3389/fmed.2024.1365524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Accepted: 04/22/2024] [Indexed: 05/25/2024] Open
Abstract
Precision medicine, characterized by the personalized integration of a patient's genetic blueprint and clinical history, represents a dynamic paradigm in healthcare evolution. The emerging field of personalized anesthesia is at the intersection of genetics and anesthesiology, where anesthetic care will be tailored to an individual's genetic make-up, comorbidities and patient-specific factors. Genomics and biomarkers can provide more accurate anesthetic protocols, while artificial intelligence can simplify anesthetic procedures and reduce anesthetic risks, and real-time monitoring tools can improve perioperative safety and efficacy. The aim of this paper is to present and summarize the applications of these related fields in anesthesiology by reviewing them, exploring the potential of advanced technologies in the implementation and development of personalized anesthesia, realizing the future integration of new technologies into clinical practice, and promoting multidisciplinary collaboration between anesthesiology and disciplines such as genomics and artificial intelligence.
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Affiliation(s)
- Shiyue Zeng
- Zhuzhou Clinical College, Jishou University, Jishou, China
| | - Qi Qing
- Zhuzhou Clinical College, Jishou University, Jishou, China
| | - Wei Xu
- Department of Anesthesiology, Zhuzhou Central Hospital, Zhuzhou, China
| | - Simeng Yu
- Zhuzhou Clinical College, Jishou University, Jishou, China
| | - Mingzhi Zheng
- Department of Anesthesiology, Zhuzhou Central Hospital, Zhuzhou, China
| | - Hongpei Tan
- Department of Radiology, Third Xiangya Hospital, Central South University, Changsha, China
| | - Junmin Peng
- Department of Anesthesiology, Zhuzhou Central Hospital, Zhuzhou, China
| | - Jing Huang
- Department of Anesthesiology, Zhuzhou Central Hospital, Zhuzhou, China
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10
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Gilbert PB, Fong Y, Hejazi NS, Kenny A, Huang Y, Carone M, Benkeser D, Follmann D. Four statistical frameworks for assessing an immune correlate of protection (surrogate endpoint) from a randomized, controlled, vaccine efficacy trial. Vaccine 2024; 42:2181-2190. [PMID: 38458870 PMCID: PMC10999339 DOI: 10.1016/j.vaccine.2024.02.071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 02/22/2024] [Accepted: 02/23/2024] [Indexed: 03/10/2024]
Abstract
A central goal of vaccine research is to characterize and validate immune correlates of protection (CoPs). In addition to helping elucidate immunological mechanisms, a CoP can serve as a valid surrogate endpoint for an infectious disease clinical outcome and thus qualifies as a primary endpoint for vaccine authorization or approval without requiring resource-intensive randomized, controlled phase 3 trials. Yet, it is challenging to persuasively validate a CoP, because a prognostic immune marker can fail as a reliable basis for predicting/inferring the level of vaccine efficacy against a clinical outcome, and because the statistical analysis of phase 3 trials only has limited capacity to disentangle association from cause. Moreover, the multitude of statistical methods garnered for CoP evaluation in phase 3 trials renders the comparison, interpretation, and synthesis of CoP results challenging. Toward promoting broader harmonization and standardization of CoP evaluation, this article summarizes four complementary statistical frameworks for evaluating CoPs in a phase 3 trial, focusing on the frameworks' distinct scientific objectives as measured and communicated by distinct causal vaccine efficacy parameters. Advantages and disadvantages of the frameworks are considered, dependent on phase 3 trial context, and perspectives are offered on how the frameworks can be applied and their results synthesized.
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Affiliation(s)
- Peter B Gilbert
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA; Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA; Department of Biostatistics, School of Public Health, University of Washington, Seattle, WA, USA.
| | - Youyi Fong
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA; Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA; Department of Biostatistics, School of Public Health, University of Washington, Seattle, WA, USA
| | - Nima S Hejazi
- Department of Biostatistics, T.H. Chan School of Public Health, Harvard University, Boston, MA, USA
| | - Avi Kenny
- Department of Biostatistics, School of Public Health, University of Washington, Seattle, WA, USA
| | - Ying Huang
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA; Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA; Department of Biostatistics, School of Public Health, University of Washington, Seattle, WA, USA
| | - Marco Carone
- Department of Biostatistics, School of Public Health, University of Washington, Seattle, WA, USA
| | - David Benkeser
- Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA, USA
| | - Dean Follmann
- Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA
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Pathak A, Pal AK, Roy S, Nandave M, Jain K. Role of Angiogenesis and Its Biomarkers in Development of Targeted Tumor Therapies. Stem Cells Int 2024; 2024:9077926. [PMID: 38213742 PMCID: PMC10783989 DOI: 10.1155/2024/9077926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Revised: 11/21/2023] [Accepted: 12/04/2023] [Indexed: 01/13/2024] Open
Abstract
Angiogenesis plays a significant role in the human body, from wound healing to tumor progression. "Angiogenic switch" indicates a time-restricted event where the imbalance between pro- and antiangiogenic factors results in the transition from prevascular hyperplasia to outgrowing vascularized tumor, which eventually leads to the malignant cancer progression. In the last decade, molecular players, i.e., angiogenic biomarkers and underlying molecular pathways involved in tumorigenesis, have been intensely investigated. Disrupting the initiation and halting the progression of angiogenesis by targeting these biomarkers and molecular pathways has been considered as a potential treatment approach for tumor angiogenesis. This review discusses the currently known biomarkers and available antiangiogenic therapies in cancer, i.e., monoclonal antibodies, aptamers, small molecular inhibitors, miRNAs, siRNAs, angiostatin, endostatin, and melatonin analogues, either approved by the U.S. Food and Drug Administration or currently under clinical and preclinical investigations.
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Affiliation(s)
- Anchal Pathak
- Drug Delivery and Nanomedicine Research Laboratory, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER)-Raebareli, Lucknow, India
| | - Ajay Kumar Pal
- Department of Pharmacology, Delhi Pharmaceutical Sciences and Research University (DPSRU), New Delhi 110017, India
| | - Subhadeep Roy
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Kolkata, West Bengal, India
| | - Mukesh Nandave
- Department of Pharmacology, Delhi Pharmaceutical Sciences and Research University (DPSRU), New Delhi 110017, India
| | - Keerti Jain
- Drug Delivery and Nanomedicine Research Laboratory, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER)-Raebareli, Lucknow, India
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12
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Sharpless LK, Kesselheim AS, Orr SL, Darrow J. Variation in Endpoints in FDA Medication Approvals: A Review of Acute and Preventive Migraine Medications. Neurology 2023; 101:e989-e1000. [PMID: 37438124 PMCID: PMC10491441 DOI: 10.1212/wnl.0000000000207544] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 05/05/2023] [Indexed: 07/14/2023] Open
Abstract
BACKGROUND AND OBJECTIVE To assess the characteristics and extent of variation of the endpoints used in trials supporting the US Food and Drug Administration (FDA) approval of medications treating migraine. METHODS Using the Drugs@FDA online database, we identified novel prescription medications approved by the FDA between January 2001 and September 2022, for migraine with or without aura, for both acute and preventive treatment, and for episodic and chronic presentations. For each medication, we used the most recent FDA-approved labeling to identify indication, mechanism of action, mode of administration, manufacturer, approval year, number of pivotal trials, trial design, and primary endpoints. RESULTS Sixteen FDA-approved medications for the acute or preventive treatment of migraine were supported by 45 pivotal trials. There were 5 primary endpoint types: (1) change in mean monthly migraine days from baseline; (2) change in mean monthly migraine attacks from baseline; (3) change in mean monthly headache days from baseline; (4) mild to no pain After 2 hours; (5) pain free at 2 hours. There were 3 combinations of coprimary endpoints: (1) Headache Pain Free at 2 Hours and Most Bothersome Symptom Free at 2 Hours; (2) Pain Free at 2 Hours and Sustained Pain Free from 2-24 Hours Postdose; (3) Pain Free at 2 Hours and 2-24 Hours Sustained Pain Free and 2-Hour Pain Relief. Of the 8 preventive migraine medications, the timing of endpoint measurement included the full double-blind period, segments of the double-blind period, and the final month of the double-blind period. DISCUSSION Migraine medication trial endpoints were inconsistent within the same indication (episodic or chronic), mechanistic class, and route of administration, frustrating direct comparison among these medications. Furthermore, inconsistent definitions for the indications "episodic" and "chronic" migraine were also observed. Consistent endpoint selection for medications approved for preventive and acute migraine treatment would enhance the ability of patients, physicians, and payers to make informed choices among these medications.
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Affiliation(s)
- Leigh K Sharpless
- From the Faculty of Arts and Sciences (L.K.S.), Harvard University, Cambridge; Division of Pharmacoepidemiology and Pharmacoeconomics (L.K.S., A.S.K., J.D.), Department of Medicine, Brigham and Women's Hospital, Boston, MA; Alberta Children's Hospital Research Institute (S.L.O.), Pediatrics; and University of Calgary (S.L.O.), Cumming School of Medicine, Alberta, Canada
| | - Aaron S Kesselheim
- From the Faculty of Arts and Sciences (L.K.S.), Harvard University, Cambridge; Division of Pharmacoepidemiology and Pharmacoeconomics (L.K.S., A.S.K., J.D.), Department of Medicine, Brigham and Women's Hospital, Boston, MA; Alberta Children's Hospital Research Institute (S.L.O.), Pediatrics; and University of Calgary (S.L.O.), Cumming School of Medicine, Alberta, Canada
| | - Serena L Orr
- From the Faculty of Arts and Sciences (L.K.S.), Harvard University, Cambridge; Division of Pharmacoepidemiology and Pharmacoeconomics (L.K.S., A.S.K., J.D.), Department of Medicine, Brigham and Women's Hospital, Boston, MA; Alberta Children's Hospital Research Institute (S.L.O.), Pediatrics; and University of Calgary (S.L.O.), Cumming School of Medicine, Alberta, Canada
| | - Jonathan Darrow
- From the Faculty of Arts and Sciences (L.K.S.), Harvard University, Cambridge; Division of Pharmacoepidemiology and Pharmacoeconomics (L.K.S., A.S.K., J.D.), Department of Medicine, Brigham and Women's Hospital, Boston, MA; Alberta Children's Hospital Research Institute (S.L.O.), Pediatrics; and University of Calgary (S.L.O.), Cumming School of Medicine, Alberta, Canada.
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13
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Fischer PR, Johnson CR, Leopold KN, Thacher TD. Treatment of vitamin D deficiency in children. Expert Rev Endocrinol Metab 2023; 18:489-502. [PMID: 37861060 DOI: 10.1080/17446651.2023.2270053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Accepted: 10/09/2023] [Indexed: 10/21/2023]
Abstract
INTRODUCTION Vitamin D deficiency affects from 10% to 50% in various pediatric population groups and causes life-threatening hypocalcemia in infants, crippling rickets in infants and children, and increased risk of subsequent adult metabolic and neurologic problems. AREAS COVERED An English language literature search of PubMed was performed since 1940 as were the authors' personal literature collections. References identified in the reviewed literature are considered. DIAGNOSIS The diagnosis of vitamin D deficiency is based on serum 25-hydroxyvitamin D levels. Clinical features of rickets include bone deformities and elevated alkaline phosphatase. Most children and adolescents who are biochemically vitamin D deficient do not have specific symptoms or signs of deficiency. PREVENTION Prevention of vitamin D deficiency is via exposure to sunshine, food and beverage fortification, and dietary supplementation. TREATMENT Effective treatment of vitamin D deficiency is via oral or injectable administration of vitamin D. Dosing and duration of vitamin D therapy have been described for healthy children and for children with underlying medical conditions, but recommendations vary. EXPERT OPINION Further investigation is needed to determine long-term non-skeletal effects of childhood vitamin D deficiency, benefits of supplementation in asymptomatic individuals with biochemical vitamin D deficiency, and appropriate screening for vitamin D deficiency in asymptomatic children and adolescents.
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Affiliation(s)
- Philip R Fischer
- Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN USA
- Sheikh Shakhbout Medical City, Abu Dhabi, UAE
- Khalifa University College of Health and Medical Science, Abu Dhabi, UAE
| | - Casey R Johnson
- Pediatric Gastroenterology and Nutrition, Boston Children's Hospital, Boston, MN, USA
| | - Kaitlin N Leopold
- Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN USA
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14
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Cimino J, Braun C. Design a Clinical Research Protocol: Influence of Real-World Setting. Healthcare (Basel) 2023; 11:2254. [PMID: 37628452 PMCID: PMC10454664 DOI: 10.3390/healthcare11162254] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 08/03/2023] [Accepted: 08/09/2023] [Indexed: 08/27/2023] Open
Abstract
The design of a clinical research protocol to evaluate new therapies, devices, patient quality of life, and medical practices from scratch is probably one of the greatest challenges for the majority of novice researchers. This is especially true since a high-quality methodology is required to achieve success and effectiveness in academic and hospital research centers. This review discusses the concrete steps and necessary guidelines needed to create and structure a research protocol. Along with the methodology, some administrative challenges (ethics, regulatory and people-management barriers) and possible time-saving recommendations (standardized procedures, collaborative training, and centralization) are discussed.
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Affiliation(s)
- Jonathan Cimino
- Clinical Research Unit, Fondation Hôpitaux Robert Schuman, 44 Rue d’Anvers, 1130 Luxembourg, Luxembourg;
- Hôpitaux Robert Schuman, 9 Rue Edward Steichen, 2540 Luxembourg, Luxembourg
| | - Claude Braun
- Clinical Research Unit, Fondation Hôpitaux Robert Schuman, 44 Rue d’Anvers, 1130 Luxembourg, Luxembourg;
- Hôpitaux Robert Schuman, 9 Rue Edward Steichen, 2540 Luxembourg, Luxembourg
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15
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Di Nunno V, Gatto L, Tosoni A, Bartolini S, Franceschi E. Letter concerning "Objective response rate targets for recurrent glioblastoma clinical trials based on the historic association between ORR and median overall survival": Toward surrogate endpoints for phase II trials in patients with recurrent glioblastoma. Neuro Oncol 2023; 25:1546-1547. [PMID: 37171969 PMCID: PMC10398804 DOI: 10.1093/neuonc/noad071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/14/2023] Open
Affiliation(s)
- Vincenzo Di Nunno
- Department of Oncology, Azienda Unità Sanitaria Locale (AUSL) Bologna, 40139 Bologna, Italy
| | - Lidia Gatto
- Department of Oncology, Azienda Unità Sanitaria Locale (AUSL) Bologna, 40139 Bologna, Italy
| | - Alicia Tosoni
- Nervous System Medical Oncology Department, IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
| | - Stefania Bartolini
- Nervous System Medical Oncology Department, IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
| | - Enrico Franceschi
- Nervous System Medical Oncology Department, IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
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16
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Ciani O, Manyara AM, Taylor RS. Surrogate end points in cardio-thoracic trials: a call for better reporting and improved interpretation of trial findings. EUROPEAN JOURNAL OF CARDIO-THORACIC SURGERY : OFFICIAL JOURNAL OF THE EUROPEAN ASSOCIATION FOR CARDIO-THORACIC SURGERY 2022; 62:6702080. [PMID: 36112148 DOI: 10.1093/ejcts/ezac449] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 08/28/2022] [Indexed: 11/14/2022]
Affiliation(s)
- Oriana Ciani
- Center for Research on Health and Social Care Management, SDA Bocconi School of Management, Milan, Italy
| | - Anthony Muchai Manyara
- MRC/CSO Social and Public Health Sciences Unit, Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK
| | - Rod S Taylor
- MRC/CSO Social and Public Health Sciences Unit, Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK.,Robertson Centre for Biostatistics, Institute of Health and Well Being, University of Glasgow, Glasgow, UK
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17
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Ciani O, Grigore B, Taylor RS. Development of a framework and decision tool for the evaluation of health technologies based on surrogate endpoint evidence. HEALTH ECONOMICS 2022; 31 Suppl 1:44-72. [PMID: 35608044 PMCID: PMC9546394 DOI: 10.1002/hec.4524] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 11/28/2021] [Accepted: 04/02/2022] [Indexed: 05/27/2023]
Abstract
In the drive toward faster patient access to treatments, health technology assessment (HTA) agencies and payers are increasingly faced with reliance on evidence based on surrogate endpoints, increasing decision uncertainty. Despite the development of a small number of evaluation frameworks, there remains no consensus on the detailed methodology for handling surrogate endpoints in HTA practice. This research overviews the methods and findings of four empirical studies undertaken as part of COMED (Pushing the Boundaries of Cost and Outcome Analysis of Medical Technologies) program work package 2 with the aim of analyzing international HTA practice of the handling and considerations around the use of surrogate endpoint evidence. We have synthesized the findings of these empirical studies, in context of wider contemporary body of methodological and policy-related literature on surrogate endpoints, to develop a web-based decision tool to support HTA agencies and payers when faced with surrogate endpoint evidence. Our decision tool is intended for use by HTA agencies and their decision-making committees together with the wider community of HTA stakeholders (including clinicians, patient groups, and healthcare manufacturers). Having developed this tool, we will monitor its use and we welcome feedback on its utility.
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Affiliation(s)
- Oriana Ciani
- Centre for Research on Health and Social Care ManagementSDA BocconiMilanLombardiaItaly
- Evidence Synthesis & Modelling for Health ImprovementCollege of Medicine and HealthUniversity of ExeterExeterDevonUK
| | - Bogdan Grigore
- Exeter Test GroupCollege of Medicine and HealthUniversity of ExeterExeterDevonUK
| | - Rod S. Taylor
- MRC/CSO Social and Public Health Sciences Unit & Robertson Centre for BiostatisticsInstitute of Health and Well BeingUniversity of GlasgowGlasgowScotlandUK
- College of Medicine and HealthUniversity of ExeterExeterDevonUK
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18
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Webber HE, de Dios C, Kessler DA, Schmitz JM, Lane SD, Suchting R. Late positive potential as a candidate biomarker of motivational relevance in substance use: Evidence from a meta-analysis. Neurosci Biobehav Rev 2022; 141:104835. [PMID: 36031010 DOI: 10.1016/j.neubiorev.2022.104835] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 08/19/2022] [Accepted: 08/20/2022] [Indexed: 10/15/2022]
Abstract
The objective of the current meta-analysis was to assess the effect size of the Late Positive Potential (LPP) to drug and emotional cues in substance users compared to controls. The secondary objective was to test for moderation by: age, gender, years of use, use status, and substance type. Search was performed in August 2021 using PubMed. Inclusion criteria were: substance use disorder/dependence or validated self-report, LPP means, healthy control comparison, non-acute drug study, data available, peer-reviewed journal, English, and human participants. Selection bias was tested through modified Egger's regression and exploratory 3-parameter selection model tests. Results (k = 11) indicated LPP to drug cues was larger in substance use compared to control group, with a large effect size (Hedges' g=1.66, 95%CI [0.64,2.67], p = 0.005). There were no overall differences for emotional cues. Though threats of selection bias were not severe, inclusion of more studies with larger sample sizes in future meta-analyses will allow more robust tests of publication bias and more accurate measures of effect size.
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Affiliation(s)
- Heather E Webber
- Faillace Department of Psychiatry and Behavioral Sciences, University of Texas Health Science Center at Houston, 1941 East Road, Houston, TX 77054, USA.
| | - Constanza de Dios
- Faillace Department of Psychiatry and Behavioral Sciences, University of Texas Health Science Center at Houston, 1941 East Road, Houston, TX 77054, USA
| | - Danielle A Kessler
- College of Medicine at Tower Health, Drexel University, 50 Innovation Way, Wyomissing, PA 19610, USA
| | - Joy M Schmitz
- Faillace Department of Psychiatry and Behavioral Sciences, University of Texas Health Science Center at Houston, 1941 East Road, Houston, TX 77054, USA
| | - Scott D Lane
- Faillace Department of Psychiatry and Behavioral Sciences, University of Texas Health Science Center at Houston, 1941 East Road, Houston, TX 77054, USA
| | - Robert Suchting
- Faillace Department of Psychiatry and Behavioral Sciences, University of Texas Health Science Center at Houston, 1941 East Road, Houston, TX 77054, USA
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19
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Naffouje SA, Manguso N, Imanirad I, Sahin IH, Xie H, Hoffe S, Frakes J, Sanchez J, Dessureault S, Felder S. Neoadjuvant rectal score is prognostic for survival: A population-based propensity-matched analysis. J Surg Oncol 2022; 126:1219-1231. [PMID: 35916542 DOI: 10.1002/jso.27020] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Accepted: 07/09/2022] [Indexed: 11/07/2022]
Abstract
INTRODUCTION Neoadjuvant rectal (NAR) score may serve as a surrogate short-term endpoint for overall survival (OS) in clinical trials. This study aims to test the NAR score using a large, national cancer registry. METHODS National Cancer Database patients with clinical stage II/III rectal adenocarcinoma (RAC) treated with neoadjuvant chemoradiation (CRT) followed by surgery were selected and divided into low-, intermediate-, and high-NAR subgroups. OS outcomes were analyzed using Kaplan-Meier and logistic regression models. RESULTS A total of 12 452 patients were selected, of which 5071 (40.7%) were in clinical stage II and 7381 (59.3%) were in clinical stage III; 15.2% had pathologic complete response. The mean NAR score was 10.01 ± 10.61. Six thousand nine hundred and forty-one (55.7%) did not receive adjuvant chemotherapy (AC) and were propensity-matched across NAR subgroups (966 in each group). A significant difference in 5-year OS between low-, intermediate-, and high-NAR groups was observed (85% vs. 76% vs. 68%; p < 0.001). Five thousand five hundred and eleven (44.3%) received AC and 1045 triplets were propensity-matched per NAR groups. A significant difference was again observed for 5-year OS (93% vs. 88% vs. 75%; p < 0.001). Logistic regression confirmed NAR strata as a significant predictor of 5-year OS. CONCLUSION NAR score, as a neoadjuvant response measure, is a strong predictor of 5-year OS, regardless of AC receipt in a heterogenous population of locally advanced RAC patients.
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Affiliation(s)
- Samer A Naffouje
- Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, Florida, USA
| | - Nicholas Manguso
- Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, Florida, USA
| | - Iman Imanirad
- Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, Florida, USA
| | - Ibrahim H Sahin
- Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, Florida, USA
| | - Hao Xie
- Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, Florida, USA
| | - Sarah Hoffe
- Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, Florida, USA
| | - Jessica Frakes
- Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, Florida, USA
| | - Julian Sanchez
- Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, Florida, USA
| | - Sophie Dessureault
- Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, Florida, USA
| | - Seth Felder
- Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, Florida, USA
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20
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Lange KW. Tea in cardiovascular health and disease: a critical appraisal of the evidence. FOOD SCIENCE AND HUMAN WELLNESS 2022. [DOI: 10.1016/j.fshw.2021.12.034] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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21
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Blomsma N, de Rooy B, Gerritse F, van der Spek R, Tewarie P, Hillebrand A, Otte WM, Stam CJ, van Dellen E. Minimum spanning tree analysis of brain networks: A systematic review
of network size effects, sensitivity for neuropsychiatric pathology and disorder
specificity. Netw Neurosci 2022; 6:301-319. [PMID: 35733422 PMCID: PMC9207994 DOI: 10.1162/netn_a_00245] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Accepted: 03/10/2022] [Indexed: 11/05/2022] Open
Abstract
Brain network characteristics’ potential to serve as a neurological and psychiatric pathology biomarker has been hampered by the so-called thresholding problem. The minimum spanning tree (MST) is increasingly applied to overcome this problem. It is yet unknown whether this approach leads to more consistent findings across studies and converging outcomes of either disease-specific biomarkers or transdiagnostic effects. We performed a systematic review on MST analysis in neurophysiological and neuroimaging studies (N = 43) to study consistency of MST metrics between different network sizes and assessed disease specificity and transdiagnostic sensitivity of MST metrics for neurological and psychiatric conditions. Analysis of data from control groups (12 studies) showed that MST leaf fraction but not diameter decreased with increasing network size. Studies showed a broad range in metric values, suggesting that specific processing pipelines affect MST topology. Contradicting findings remain in the inconclusive literature of MST brain network studies, but some trends were seen: (1) a more linelike organization characterizes neurodegenerative disorders across pathologies, and is associated with symptom severity and disease progression; (2) neurophysiological studies in epilepsy show frequency band specific MST alterations that normalize after successful treatment; and (3) less efficient MST topology in alpha band is found across disorders associated with attention impairments. The potential of brain network characteristics to serve as biomarker of neurological and psychiatric pathology has been hampered by the so-called thresholding problem. The minimum spanning tree (MST) is increasingly applied to overcome this problem. We performed a systematic review on MST analysis in neurophysiological and neuroimaging studies and assessed disease specificity and transdiagnostic sensitivity of MST metrics for neurological and psychiatric conditions. MST leaf fraction but not diameter decreased with increasing network size. Contradicting findings remain in the literature on MST brain network studies, but some trends were seen: (1) a more linelike organization characterizes neurodegenerative disorders; (2) in epilepsy there are frequency band specific MST alterations that normalize after successful treatment; and (3) less efficient MST topology is found across disorders associated with attention impairments.
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Affiliation(s)
- Nicky Blomsma
- University Medical Center Utrecht, Department of Psychiatry, Brain Center, Heidelberglaan 100, Utrecht, the Netherlands
| | - Bart de Rooy
- University Medical Center Utrecht, Department of Psychiatry, Brain Center, Heidelberglaan 100, Utrecht, the Netherlands
| | - Frank Gerritse
- University Medical Center Utrecht, Department of Psychiatry, Brain Center, Heidelberglaan 100, Utrecht, the Netherlands
| | - Rick van der Spek
- University Medical Center Utrecht, Department of Psychiatry, Brain Center, Heidelberglaan 100, Utrecht, the Netherlands
| | - Prejaas Tewarie
- Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Neurology and Department of Clinical Neurophysiology and MEG center, Amsterdam Neuroscience, De Boelelaan 1117, Amsterdam, The Netherlands
| | - Arjan Hillebrand
- Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Neurology and Department of Clinical Neurophysiology and MEG center, Amsterdam Neuroscience, De Boelelaan 1117, Amsterdam, The Netherlands
| | - Wim M. Otte
- University Medical Center Utrecht, Department of Child Neurology, Brain Center, Heidelberglaan 100, Utrecht, the Netherlands
| | - Cornelis Jan Stam
- Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Neurology and Department of Clinical Neurophysiology and MEG center, Amsterdam Neuroscience, De Boelelaan 1117, Amsterdam, The Netherlands
| | - Edwin van Dellen
- University Medical Center Utrecht, Department of Psychiatry, Brain Center, Heidelberglaan 100, Utrecht, the Netherlands
- University Medical Center Utrecht, Department of Intensive Care Medicine, Brain Center, Heidelberglaan 100, Utrecht, the Netherlands
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22
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Kouroumalis E, Voumvouraki A. Hepatitis C virus: A critical approach to who really needs treatment. World J Hepatol 2022; 14:1-44. [PMID: 35126838 PMCID: PMC8790391 DOI: 10.4254/wjh.v14.i1.1] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 04/14/2021] [Accepted: 12/31/2021] [Indexed: 02/06/2023] Open
Abstract
Introduction of effective drugs in the treatment of hepatitis C virus (HCV) infection has prompted the World Health Organization to declare a global eradication target by 2030. Propositions have been made to screen the general population and treat all HCV carriers irrespective of the disease status. A year ago the new severe acute respiratory syndrome coronavirus 2 virus appeared causing a worldwide pandemic of coronavirus disease 2019 disease. Huge financial resources were redirected, and the pandemic became the first priority in every country. In this review, we examined the feasibility of the World Health Organization elimination program and the actual natural course of HCV infection. We also identified and analyzed certain comorbidity factors that may aggravate the progress of HCV and some marginalized subpopulations with characteristics favoring HCV dissemination. Alcohol consumption, HIV coinfection and the presence of components of metabolic syndrome including obesity, hyperuricemia and overt diabetes were comorbidities mostly responsible for increased liver-related morbidity and mortality of HCV. We also examined the significance of special subpopulations like people who inject drugs and males having sex with males. Finally, we proposed a different micro-elimination screening and treatment program that can be implemented in all countries irrespective of income. We suggest that screening and treatment of HCV carriers should be limited only in these particular groups.
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Affiliation(s)
- Elias Kouroumalis
- Department of Gastroenterology, University of Crete Medical School, Heraklion 71500, Crete, Greece
| | - Argyro Voumvouraki
- First Department of Internal Medicine, AHEPA University Hospital, Thessaloniki 54621, Greece
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23
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Refining neoadjuvant therapy clinical trial design for muscle-invasive bladder cancer before cystectomy: a joint US Food and Drug Administration and Bladder Cancer Advocacy Network workshop. Nat Rev Urol 2022; 19:37-46. [PMID: 34508246 DOI: 10.1038/s41585-021-00505-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/13/2021] [Indexed: 02/08/2023]
Abstract
The success of the use of novel therapies in the treatment of advanced urothelial carcinoma has contributed to growing interest in evaluating these therapies at earlier stages of the disease. However, trials evaluating these therapies in the neoadjuvant setting must have clearly defined study elements and appropriately selected end points to ensure the applicability of the trial and enable interpretation of the study results. To advance the development of rational trial design, a public workshop jointly sponsored by the US Food and Drug Administration and the Bladder Cancer Advocacy Network convened in August 2019. Clinicians, clinical trialists, radiologists, biostatisticians, patients, advocates and other stakeholders discussed key elements and end points when designing trials of neoadjuvant therapy for muscle-invasive bladder cancer (MIBC), identifying opportunities to refine eligibility, design and end points for neoadjuvant trials in MIBC. Although pathological complete response (pCR) is already being used as a co-primary end point, both individual-level and trial-level surrogacy for time-to-event end points, such as event-free survival or overall survival, remain incompletely characterized in MIBC. Additionally, use of pCR is limited by heterogeneity in pathological evaluation and the fact that the magnitude of pCR improvement that might translate into a meaningful clinical benefit remains unclear. Given existing knowledge gaps, capture of highly granular patient-related, tumour-related and treatment-related characteristics in the current generation of neoadjuvant MIBC trials will be critical to informing the design of future trials.
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24
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De Picker LJ, Haarman BCM. Applicability, potential and limitations of TSPO PET imaging as a clinical immunopsychiatry biomarker. Eur J Nucl Med Mol Imaging 2021; 49:164-173. [PMID: 33735406 DOI: 10.1007/s00259-021-05308-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Accepted: 03/08/2021] [Indexed: 02/08/2023]
Abstract
PURPOSE TSPO PET imaging may hold promise as a single-step diagnostic work-up for clinical immunopsychiatry. This review paper on the clinical applicability of TSPO PET for primary psychiatric disorders discusses if and why TSPO PET imaging might become the first clinical immunopsychiatry biomarker and the investment prerequisites and scientific advancements needed to accommodate this transition from bench to bedside. METHODS We conducted a systematic search of the literature to identify clinical studies of TSPO PET imaging in patients with primary psychiatric disorders. We included both original case-control studies as well as longitudinal cohort studies of patients with a primary psychiatric diagnosis. RESULTS Thirty-one original studies met our inclusion criteria. In the field of immunopsychiatry, TSPO PET has until now mostly been studied in schizophrenia and related psychotic disorders, and to a lesser extent in mood disorders and neurodevelopmental disorders. Quantitative TSPO PET appears most promising as a predictive biomarker for the transdiagnostic identification of subgroups or disease stages that could benefit from immunological treatments, or as a prognostic biomarker forecasting patients' illness course. Current scanning protocols are still too unreliable, impractical and invasive for clinical use in symptomatic psychiatric patients. CONCLUSION TSPO PET imaging in its present form does not yet offer a sufficiently attractive cost-benefit ratio to become a clinical immunopsychiatry biomarker. Its translation to psychiatric clinical practice will depend on the prioritising of longitudinal research and the establishment of a uniform protocol rendering clinically meaningful TSPO uptake quantification at the shortest possible scan duration without arterial cannulation.
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Affiliation(s)
- Livia J De Picker
- University Psychiatric Hospital Campus Duffel, Stationsstraat 22C, 2570, Duffel, Belgium.
- Collaborative Antwerp Psychiatric Research Institute, University of Antwerp, Wilrijkstraat 1, 2650, Edegem, Belgium.
| | - Benno C M Haarman
- Department of Psychiatry, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700RA, Groningen, The Netherlands
- Rob Giel Research Center (RGOc), University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700RA, Groningen, The Netherlands
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25
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Lands B. Lipid nutrition: "In silico" studies and undeveloped experiments. Prog Lipid Res 2021; 85:101142. [PMID: 34818526 DOI: 10.1016/j.plipres.2021.101142] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 11/11/2021] [Accepted: 11/12/2021] [Indexed: 12/14/2022]
Abstract
This review examines lipids and lipid-binding sites on proteins in relation to cardiovascular disease. Lipid nutrition involves food energy from ingested fatty acids plus fatty acids formed from excess ingested carbohydrate and protein. Non-esterified fatty acids (NEFA) and lipoproteins have many detailed attributes not evident in their names. Recognizing attributes of lipid-protein interactions decreases unexpected outcomes. Details of double bond position and configuration interacting with protein binding sites have unexpected consequences in acyltransferase and cell replication events. Highly unsaturated fatty acids (HUFA) have n-3 and n-6 motifs with documented differences in intensity of destabilizing positive feedback loops amplifying pathophysiology. However, actions of NEFA have been neglected relative to cholesterol, which is co-produced from excess food. Native low-density lipoproteins (LDL) bind to a high-affinity cell surface receptor which poorly recognizes biologically modified LDLs. NEFA increase negative charge of LDL and decrease its processing by "normal" receptors while increasing processing by "scavenger" receptors. A positive feedback loop in the recruitment of monocytes and macrophages amplifies chronic inflammatory pathophysiology. Computer tools combine multiple components in lipid nutrition and predict balance of energy and n-3:n-6 HUFA. The tools help design and execute precise clinical nutrition monitoring that either supports or disproves expectations.
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Affiliation(s)
- Bill Lands
- Fellow ASN, AAAS, SFRBM, ISSFAL, College Park, MD, USA.
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26
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Duke ER, Williamson BD, Borate B, Golob JL, Wychera C, Stevens-Ayers T, Huang ML, Cossrow N, Wan H, Mast TC, Marks MA, Flowers ME, Jerome KR, Corey L, Gilbert PB, Schiffer JT, Boeckh M. CMV viral load kinetics as surrogate endpoints after allogeneic transplantation. J Clin Invest 2021; 131:133960. [PMID: 32970635 DOI: 10.1172/jci133960] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Accepted: 09/17/2020] [Indexed: 12/19/2022] Open
Abstract
BACKGROUNDViral load (VL) surrogate endpoints transformed development of HIV and hepatitis C therapeutics. Surrogate endpoints for CMV-related morbidity and mortality could advance development of antiviral treatments. Although observational data support using CMV VL as a trial endpoint, randomized controlled trials (RCTs) demonstrating direct associations between virological markers and clinical endpoints are lacking.METHODSWe performed CMV DNA PCR on frozen serum samples from the only placebo-controlled RCT of ganciclovir for early treatment of CMV after hematopoietic cell transplantation (HCT). We used established criteria to assess VL kinetics as surrogates for CMV disease or death by weeks 8, 24, and 48 after randomization and quantified antiviral effects captured by each marker. We used ensemble-based machine learning to assess the predictive ability of VL kinetics and performed this analysis on a ganciclovir prophylaxis RCT for validation.RESULTSVL suppression with ganciclovir reduced cumulative incidence of CMV disease and death for 20 years after HCT. Mean VL, peak VL, and change in VL during the first 5 weeks of treatment fulfilled the Prentice definition for surrogacy, capturing more than 95% of ganciclovir's effect, and yielded highly sensitive and specific predictions by week 48. In the prophylaxis trial, the viral shedding rate satisfied the Prentice definition for CMV disease by week 24.CONCLUSIONSOur results support using CMV VL kinetics as surrogates for CMV disease, provide a framework for developing CMV preventative and therapeutic agents, and support reductions in VL as the mechanism through which antivirals reduce CMV disease.FUNDINGMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
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Affiliation(s)
- Elizabeth R Duke
- Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.,University of Washington, Seattle, Washington, USA
| | | | - Bhavesh Borate
- Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - Jonathan L Golob
- Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.,University of Washington, Seattle, Washington, USA
| | - Chiara Wychera
- Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | | | | | | | - Hong Wan
- Merck & Co., Inc., Kenilworth, New Jersey, USA
| | | | | | - Mary E Flowers
- Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.,University of Washington, Seattle, Washington, USA
| | - Keith R Jerome
- Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.,University of Washington, Seattle, Washington, USA
| | - Lawrence Corey
- Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.,University of Washington, Seattle, Washington, USA
| | - Peter B Gilbert
- Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.,University of Washington, Seattle, Washington, USA
| | - Joshua T Schiffer
- Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.,University of Washington, Seattle, Washington, USA
| | - Michael Boeckh
- Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.,University of Washington, Seattle, Washington, USA
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Ciani O, Grigore B, Blommestein H, de Groot S, Möllenkamp M, Rabbe S, Daubner-Bendes R, Taylor RS. Validity of Surrogate Endpoints and Their Impact on Coverage Recommendations: A Retrospective Analysis across International Health Technology Assessment Agencies. Med Decis Making 2021; 41:439-452. [PMID: 33719711 PMCID: PMC8108112 DOI: 10.1177/0272989x21994553] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Accepted: 01/21/2021] [Indexed: 12/03/2022]
Abstract
BACKGROUND Surrogate endpoints (i.e., intermediate endpoints intended to predict for patient-centered outcomes) are increasingly common. However, little is known about how surrogate evidence is handled in the context of health technology assessment (HTA). OBJECTIVES 1) To map methodologies for the validation of surrogate endpoints and 2) to determine their impact on acceptability of surrogates and coverage decisions made by HTA agencies. METHODS We sought HTA reports where evaluation relied on a surrogate from 8 HTA agencies. We extracted data on the methods applied for surrogate validation. We assessed the level of agreement between agencies and fitted mixed-effects logistic regression models to test the impact of validation approaches on the agency's acceptability of the surrogate endpoint and their coverage recommendation. RESULTS Of the 124 included reports, 61 (49%) discussed the level of evidence to support the relationship between the surrogate and the patient-centered endpoint, 27 (22%) reported a correlation coefficient/association measure, and 40 (32%) quantified the expected effect on the patient-centered outcome. Overall, the surrogate endpoint was deemed acceptable in 49 (40%) reports (k-coefficient 0.10, P = 0.004). Any consideration of the level of evidence was associated with accepting the surrogate endpoint as valid (odds ratio [OR], 4.60; 95% confidence interval [CI], 1.60-13.18, P = 0.005). However, we did not find strong evidence of an association between accepting the surrogate endpoint and agency coverage recommendation (OR, 0.71; 95% CI, 0.23-2.20; P = 0.55). CONCLUSIONS Handling of surrogate endpoint evidence in reports varied greatly across HTA agencies, with inconsistent consideration of the level of evidence and statistical validation. Our findings call for careful reconsideration of the issue of surrogacy and the need for harmonization of practices across international HTA agencies.
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Affiliation(s)
- Oriana Ciani
- />Centre for Research on Health and Social Care Management, SDA Bocconi, Milan, Lombardia, Italy
- />Evidence Synthesis & Modelling for Health Improvement, University of Exeter Medical School, Exeter, Devon, UK
| | - Bogdan Grigore
- Evidence Synthesis & Modelling for Health Improvement, University of Exeter Medical School, Exeter, Devon, UK
| | - Hedwig Blommestein
- Institute for Medical Technology Assessment, Erasmus School of Health Policy & Management, Erasmus University Rotterdam, Rotterdam, The Netherlands
| | - Saskia de Groot
- Institute for Medical Technology Assessment, Erasmus School of Health Policy & Management, Erasmus University Rotterdam, Rotterdam, The Netherlands
| | - Meilin Möllenkamp
- Hamburg Center for Health Economics, Universität Hamburg, Hamburg, Germany
| | - Stefan Rabbe
- Hamburg Center for Health Economics, Universität Hamburg, Hamburg, Germany
| | - Rita Daubner-Bendes
- />Syreon Research Institute, Budapest, Hungary
- />MRC/CSO Social and Public Health Sciences Unit & Robertson Centre for Biostatistics, Institute of Health and Well Being, University of Glasgow, Glasgow, Scotland, UK
| | - Rod S. Taylor
- />Evidence Synthesis & Modelling for Health Improvement, University of Exeter Medical School, Exeter, Devon, UK
- />MRC/CSO Social and Public Health Sciences Unit & Robertson Centre for Biostatistics, Institute of Health and Well Being, University of Glasgow, Glasgow, Scotland, UK
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28
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Matsumoto H, Horita N, Ito K, Ebina-Shibuya R, Hara Y, Kobayashi N, Kaneko T. Disease control and objective responsive rates in randomized phase II trials evaluating non-first-line chemotherapy for non-small cell lung cancer: a systematic review of 74 trials. Transl Lung Cancer Res 2021; 10:2278-2289. [PMID: 34164275 PMCID: PMC8182707 DOI: 10.21037/tlcr-20-1120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Although objective response rate and disease control rate are commonly used as primary endpoints of lung cancer trials, it remains unclear whether objective response rate and disease control rate correctly reflect the overall survival in a non-small cell lung cancer phase II trial evaluating a non-first-line chemotherapy. Objective response rate might be easily affected by chance because the small number of patients in each trial achieved complete or partial response in the phase II non-first-line setting. This study was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (UMIN000040412). Four databases were searched for eligible trials. A Spearman's rank correlation with hazard ratio of overall survival was calculated each for odds ratio of objective response rate, difference of objective response rate (%), odds ratio of disease control rate, and difference of disease control rate (%). Of 74 eligible trials, 73 reported objective response rate and 68 reported disease control rates. Nine (12%) trials included patients with driver mutation status. Thirteen (18%) and two (3%) RCTs specifically included adenocarcinoma/non-squamous and squamous subtype of non-small cell lung cancer, respectively. The Eastern Cooperative Oncology Group performance status 0-2 (N=41, 55%) and the performance status 0-1 (N=25, 34%) were frequently used performance status criteria. The median number of patients in the two arms was 116 (interquartile range, 82-159). The correlation between trial-level odds ratio of objective response rate and hazard ratio of overall survival was weak (r=-0.29, 95% CI: -0.49 to -0.05, P=0.014). An exploratory subgroup analysis suggested that fewer responders were associated with poorer correlation. Odds ratio of disease control survival (r=-0.53, 95% CI: -0.68 to -0.32, P<0.001) had moderate rank correlations with hazard ratio of overall survival. Instead of objective response rate, disease control rate should be used as the primary endpoint in a randomized phase II trial evaluating non-first-line chemotherapy for non-small cell lung cancer.
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Affiliation(s)
- Hiromi Matsumoto
- Department of Pulmonology, Yokohama City University Graduate School of Medicine. Yokohama, Japan
| | - Nobuyuki Horita
- Department of Pulmonology, Yokohama City University Graduate School of Medicine. Yokohama, Japan
| | - Kentaro Ito
- Respiratory Center, Matsusaka Municipal Hospital, Matsusaka, Japan
| | - Risa Ebina-Shibuya
- Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Yu Hara
- Department of Pulmonology, Yokohama City University Graduate School of Medicine. Yokohama, Japan
| | - Nobuaki Kobayashi
- Department of Pulmonology, Yokohama City University Graduate School of Medicine. Yokohama, Japan
| | - Takeshi Kaneko
- Department of Pulmonology, Yokohama City University Graduate School of Medicine. Yokohama, Japan
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Lok JJ, Bosch RJ. Causal Organic Indirect and Direct Effects: Closer to the Original Approach to Mediation Analysis, with a Product Method for Binary Mediators. Epidemiology 2021; 32:412-420. [PMID: 33783395 PMCID: PMC8362675 DOI: 10.1097/ede.0000000000001339] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Mediation analysis, which started in the mid-1980s, is used extensively by applied researchers. Indirect and direct effects are the part of a treatment effect that is mediated by a covariate and the part that is not. Subsequent work on natural indirect and direct effects provides a formal causal interpretation, based on cross-worlds counterfactuals: outcomes under treatment with the mediator set to its value without treatment. Organic indirect and direct effects avoid cross-worlds counterfactuals, using so-called organic interventions on the mediator while keeping the initial treatment fixed at treatment. Organic indirect and direct effects apply also to settings where the mediator cannot be set. In linear models where the outcome model does not have treatment-mediator interaction, both organic and natural indirect and direct effects lead to the same estimators as in the original formulation of mediation analysis. Here, we generalize organic interventions on the mediator to include interventions combined with the initial treatment fixed at no treatment. We show that the product method holds in linear models for organic indirect and direct effects relative to no treatment even if there is treatment-mediator interaction. Moreover, we find a product method for binary mediators. Furthermore, we argue that the organic indirect effect relative to no treatment is very relevant for drug development. We illustrate the benefits of our approach by estimating the organic indirect effect of curative HIV treatments mediated by two HIV persistence measures, using data on interruption of antiretroviral therapy without curative HIV treatments combined with an estimated or hypothesized effect of the curative HIV treatments on these mediators. See video abstract at http://links.lww.com/EDE/B796.
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Affiliation(s)
- Judith J Lok
- From the Department of Mathematics and Statistics, Boston University, Boston, MA
| | - Ronald J Bosch
- Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston, MA
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30
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Gu JJ, Liu Q, Zheng LJ. A Frailty Assessment Tool to Predict In-Hospital Mortality in Patients with Acute Exacerbations of Chronic Obstructive Pulmonary Disease. Int J Chron Obstruct Pulmon Dis 2021; 16:1093-1100. [PMID: 33907395 PMCID: PMC8068494 DOI: 10.2147/copd.s300980] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 03/21/2021] [Indexed: 01/18/2023] Open
Abstract
Background The exacerbation of chronic obstructive pulmonary disease (AECOPD) is a chronic, frequent, and life-threatening lung disease. In 2014, a frailty index (FI) based on deficits in commonly used laboratory tests (FI-Lab) was suggested to identify older adults at increased risk of death. Objective We aim to study the prognostic value of the FI-Lab in older Chinese patients who were admitted because of AECOPD. Methods We screened 1932 older patients hospitalized with AECOPD from September 2016 to June 2019 at Zhenjiang First People’s Hospital, China. A multivariate logistic regression analysis was used to identify prognostic factors for in-hospital mortality. Results A total of 77 survivors and 77 non-survivors were finally included in the study. Both the mean DECAF (including dyspnea, eosinopenia, consolidation, acidemia, and atrial fibrillation) score and the mean FI-Lab value of non-survivors were statistically higher than those of survivors (4.45 ± 0.80 versus 3.03 ± 0.90, P=0.000; 0.51 ± 0.13 versus 0.29 ± 0.10, P=0.000, respectively). Logistic regression analysis suggested that DECAF Rank and FI-Lab Rank were strongly related factors of death in AECOPD patients. The areas under the receiver-operating characteristic (ROC) curves were 0.906 for FI-Lab and 0.870 for DECAF (P=0.2991). Conclusion FI-Lab is a simple, efficient, and objective tool to stratify the risk of in-hospital mortality of AECOPD.
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Affiliation(s)
- Jin-Jin Gu
- Department of Geriatrics, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, 212002, People's Republic of China
| | - Qiang Liu
- Department of Laboratory Medicine, The Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, People's Republic of China
| | - Li-Jie Zheng
- Department of Laboratory Medicine,The Affiliated People's Hospital of Jiangsu University, Zhejiang, 212002, People's Republic of China
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31
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Levenson M, He W, Chen J, Fang Y, Faries D, Goldstein BA, Ho M, Lee K, Mishra-Kalyani P, Rockhold F, Wang H, Zink RC. Biostatistical Considerations When Using RWD and RWE in Clinical Studies for Regulatory Purposes: A Landscape Assessment. Stat Biopharm Res 2021. [DOI: 10.1080/19466315.2021.1883473] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
| | - Weili He
- Global Medical Affairs Statistics, Data and Statistical Sciences, AbbVie, North Chicago, IL
| | - Jie Chen
- Overland Pharmaceuticals, Dover, DE
| | - Yixin Fang
- Global Medical Affairs Statistics, Data and Statistical Sciences, AbbVie, North Chicago, IL
| | - Douglas Faries
- Global Statistical Sciences, Eli Lilly & Company, Indianapolis, IN
| | - Benjamin A. Goldstein
- Department of Biostatistics & Bioinformatics, Duke University, Durham, NC
- Duke Clinical Research Institute, Duke University, Durham, NC
| | | | - Kwan Lee
- Statistics and Decision Sciences, Janssen Research and Development (retired), Spring House, PA
| | | | - Frank Rockhold
- Department of Biostatistics & Bioinformatics, Duke University, Durham, NC
- Duke Clinical Research Institute, Duke University, Durham, NC
| | - Hongwei Wang
- Global Medical Affairs Statistics, Data and Statistical Sciences, AbbVie, North Chicago, IL
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32
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¿La función muscular inspiratoria podría ser un equivalente de la insuflación pulmonar en los pacientes con EPOC? OPEN RESPIRATORY ARCHIVES 2021. [PMID: 37497355 PMCID: PMC10369540 DOI: 10.1016/j.opresp.2021.100084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Introduction Chronic obstructive pulmonary disease (COPD) is the respiratory disease that causes the greatest morbidity and mortality worldwide. Lung function parameters and systemic manifestations have been defined as prognostic factors; however, they have limitations. The aim of this study was to analyze whether inspiratory muscle strength could reflect lung hyperinflation, and therefore serve as a prognostic factor in COPD patients. Method We selected COPD patients who had performed a non-invasive respiratory muscle strength assessment and lung function testing between January 2015 and October 2017. Mortality was subsequently followed up until March 1, 2020. Results We included 140 COPD patients (GOLD stage I 5%, II 73.4%, and III 21.6%), of whom 10% died during follow-up. Bronchial obstruction, defined by FEV1, was a good predictor of mortality (p = 0.004). Lung hyperinflation, defined as inspiratory capacity (IC)/total lung capacity less than 25 and IC less than 65% of predicted increased mortality in COPD patients (p = 0.001 and p = 0.06, respectively). In this cohort, inspiratory muscle strength, measured by SNIP, was not a prognostic factor (p = 0.629). Conclusion In COPD patients, lung hyperinflation is a prognostic factor, but inspiratory muscle function is not. Inspiratory muscle function in COPD patients depends not only on lung mechanics but also on intrinsic muscle factors.
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Bučková B, Brunovský M, Bareš M, Hlinka J. Predicting Sex From EEG: Validity and Generalizability of Deep-Learning-Based Interpretable Classifier. Front Neurosci 2020; 14:589303. [PMID: 33192274 PMCID: PMC7652844 DOI: 10.3389/fnins.2020.589303] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Accepted: 09/17/2020] [Indexed: 11/13/2022] Open
Abstract
Explainable artificial intelligence holds a great promise for neuroscience and plays an important role in the hypothesis generation process. We follow-up a recent machine learning-oriented study that constructed a deep convolutional neural network to automatically identify biological sex from EEG recordings in healthy individuals and highlighted the discriminative role of beta-band power. If generalizing, this finding would be relevant not only theoretically by pointing to some specific neurobiological sexual dimorphisms, but potentially also as a relevant confound in quantitative EEG diagnostic practice. To put this finding to test, we assess whether the automatic identification of biological sex generalizes to another dataset, particularly in the presence of a psychiatric disease, by testing the hypothesis of higher beta power in women compared to men on 134 patients suffering from Major Depressive Disorder. Moreover, we construct ROC curves and compare the performance of the classifiers in determining sex both before and after the antidepressant treatment. We replicate the observation of a significant difference in beta-band power between men and women, providing classification accuracy of nearly 77%. The difference was consistent across the majority of electrodes, however multivariate classification models did not generally improve the performance. Similar results were observed also after the antidepressant treatment (classification accuracy above 70%), further supporting the robustness of the initial finding.
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Affiliation(s)
- Barbora Bučková
- Department of Cybernetics, Faculty of Electrical Engineering, Czech Technical University in Prague, Prague, Czechia.,Department of Complex Systems, Institute of Computer Science of the Czech Academy of Sciences, Prague, Czechia
| | - Martin Brunovský
- National Institute of Mental Health, Klecany, Czechia.,Third Faculty of Medicine, Charles University, Prague, Czechia
| | - Martin Bareš
- National Institute of Mental Health, Klecany, Czechia.,Third Faculty of Medicine, Charles University, Prague, Czechia
| | - Jaroslav Hlinka
- Department of Complex Systems, Institute of Computer Science of the Czech Academy of Sciences, Prague, Czechia.,National Institute of Mental Health, Klecany, Czechia
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34
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Pasta G, Annunziata S, Polizzi A, Caliogna L, Jannelli E, Minen A, Mosconi M, Benazzo F, Di Minno MND. The Progression of Hemophilic Arthropathy: The Role of Biomarkers. Int J Mol Sci 2020; 21:7292. [PMID: 33023246 PMCID: PMC7583947 DOI: 10.3390/ijms21197292] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 09/28/2020] [Accepted: 09/30/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Hemophilia A and B are X-linked congenital bleeding disorders characterized by recurrent hemarthroses leading to specific changes in the synovium and cartilage, which finally result in the destruction of the joint: this process is called hemophilic arthropathy (HA). This review highlights the most prominent molecular biomarkers found in the literature to discuss their potential use in the clinical practice to monitor bleeding, to assess the progression of the HA and the effectiveness of treatments. METHODS A review of the literature was performed on PubMed and Embase, from 3 to 7 August 2020. Study selection and data extraction were achieved independently by two authors and the following inclusion criteria were determined a priori: English language, available full text and articles published in peer-reviewed journal. In addition, further articles were identified by checking the bibliography of relevant articles and searching for the studies cited in all the articles examined. RESULTS Eligible studies obtained at the end of the search and screen process were seventy-three (73). CONCLUSIONS Despite the surge of interest in the clinical use of biomarkers, current literature underlines the lack of their standardization and their potential use in the clinical practice preserving the role of physical examination and imaging in early diagnosis.
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Affiliation(s)
- Gianluigi Pasta
- Department of Orthopaedics and Traumatology, Fondazione Policlinico IRCCS San Matteo, University of Pavia, 27100 Pavia, Italy; (G.P.); (A.P.); (L.C.); (E.J.); (A.M.); (M.M.); (F.B.)
| | - Salvatore Annunziata
- Department of Orthopaedics and Traumatology, Fondazione Policlinico IRCCS San Matteo, University of Pavia, 27100 Pavia, Italy; (G.P.); (A.P.); (L.C.); (E.J.); (A.M.); (M.M.); (F.B.)
| | - Alberto Polizzi
- Department of Orthopaedics and Traumatology, Fondazione Policlinico IRCCS San Matteo, University of Pavia, 27100 Pavia, Italy; (G.P.); (A.P.); (L.C.); (E.J.); (A.M.); (M.M.); (F.B.)
| | - Laura Caliogna
- Department of Orthopaedics and Traumatology, Fondazione Policlinico IRCCS San Matteo, University of Pavia, 27100 Pavia, Italy; (G.P.); (A.P.); (L.C.); (E.J.); (A.M.); (M.M.); (F.B.)
| | - Eugenio Jannelli
- Department of Orthopaedics and Traumatology, Fondazione Policlinico IRCCS San Matteo, University of Pavia, 27100 Pavia, Italy; (G.P.); (A.P.); (L.C.); (E.J.); (A.M.); (M.M.); (F.B.)
| | - Alessandro Minen
- Department of Orthopaedics and Traumatology, Fondazione Policlinico IRCCS San Matteo, University of Pavia, 27100 Pavia, Italy; (G.P.); (A.P.); (L.C.); (E.J.); (A.M.); (M.M.); (F.B.)
| | - Mario Mosconi
- Department of Orthopaedics and Traumatology, Fondazione Policlinico IRCCS San Matteo, University of Pavia, 27100 Pavia, Italy; (G.P.); (A.P.); (L.C.); (E.J.); (A.M.); (M.M.); (F.B.)
| | - Francesco Benazzo
- Department of Orthopaedics and Traumatology, Fondazione Policlinico IRCCS San Matteo, University of Pavia, 27100 Pavia, Italy; (G.P.); (A.P.); (L.C.); (E.J.); (A.M.); (M.M.); (F.B.)
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Grigore B, Ciani O, Dams F, Federici C, de Groot S, Möllenkamp M, Rabbe S, Shatrov K, Zemplenyi A, Taylor RS. Surrogate Endpoints in Health Technology Assessment: An International Review of Methodological Guidelines. PHARMACOECONOMICS 2020; 38:1055-1070. [PMID: 32572825 DOI: 10.1007/s40273-020-00935-1] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
In the drive towards faster patient access to treatments, health technology assessment (HTA) agencies are increasingly faced with reliance on evidence from surrogate endpoints, leading to increased decision uncertainty. This study undertook an updated survey of methodological guidance for using surrogate endpoints across international HTA agencies. We reviewed HTA and economic evaluation methods guidance from European, Australian and Canadian HTA agencies. We considered how guidelines addressed the methods for handling surrogate endpoints, including (1) level of evidence, (2) methods of validation, and (3) thresholds of acceptability. Across the 73 HTA agencies surveyed, 29 (40%) had methodological guidelines that made specific reference to consideration of surrogate outcomes. Of the 45 methods documents analysed, the majority [27 (60%)] were non-technology specific, 15 (33%) focused on pharmaceuticals and three (7%) on medical devices. The principles of the European network for Health Technology Assessment (EUnetHTA) guidelines published in 2015 on the handling of surrogate endpoints appear to have been adopted by many European HTA agencies, i.e. preference for final patient-relevant outcomes and reliance on surrogate endpoints with biological plausibility and epidemiological evidence of the association between the surrogate and final endpoint. Only a small number of HTA agencies (UK National Institute for Care and Excellence; the German Institute for Medical Documentation and Information and Institute for Quality and Efficiency in Health Care; the Australian Pharmaceutical Benefits Advisory Committee; and the Canadian Agency for Drugs and Technologies in Health) have developed more detailed prescriptive criteria for the acceptance of surrogate endpoints, e.g. meta-analyses of randomised controlled trials showing strong association between the treatment effect on the surrogate and final outcomes. As the decision uncertainty associated with reliance on surrogate endpoints carries a risk to patients and society, there is a need for HTA agencies to develop more detailed methodological guidance for consistent selection and evaluation of health technologies that lack definitive final patient-relevant outcome evidence at the time of the assessment.
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Affiliation(s)
- Bogdan Grigore
- Evidence Synthesis and Modelling for Health Improvement, College of Medicine and Health, Institute of Health Research, University of Exeter, Exeter, UK.
| | - Oriana Ciani
- Evidence Synthesis and Modelling for Health Improvement, College of Medicine and Health, Institute of Health Research, University of Exeter, Exeter, UK
- Center for Research on Health and Social Care Management, SDA Bocconi, Milan, Italy
| | - Florian Dams
- KPM Center for Public Management, University of Bern, Bern, Switzerland
| | - Carlo Federici
- Center for Research on Health and Social Care Management, SDA Bocconi, Milan, Italy
| | - Saskia de Groot
- Institute for Medical Technology Assessment, Erasmus School of Health Policy and Management, Erasmus University Rotterdam, Rotterdam, The Netherlands
| | - Meilin Möllenkamp
- Hamburg Center for Health Economics, Universität Hamburg, Hamburg, Germany
| | - Stefan Rabbe
- Hamburg Center for Health Economics, Universität Hamburg, Hamburg, Germany
| | - Kosta Shatrov
- KPM Center for Public Management, University of Bern, Bern, Switzerland
| | - Antal Zemplenyi
- Syreon Research Institute, Budapest, Hungary
- Division of Pharmacoeconomics, Faculty of Pharmacy, University of Pécs, Pécs, Hungary
| | - Rod S Taylor
- Evidence Synthesis and Modelling for Health Improvement, College of Medicine and Health, Institute of Health Research, University of Exeter, Exeter, UK
- MRC/CSO Social and Public Health Sciences Unit and Robertson Centre for Biostatistics, Institute of Health and Well Being, University of Glasgow, Glasgow, Scotland
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Park J, Park S, Kim K, Hwang W, Yoo S, Yi GS, Lee D. An interactive retrieval system for clinical trial studies with context-dependent protocol elements. PLoS One 2020; 15:e0238290. [PMID: 32946464 PMCID: PMC7500653 DOI: 10.1371/journal.pone.0238290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2019] [Accepted: 08/14/2020] [Indexed: 11/19/2022] Open
Abstract
A well-defined protocol for a clinical trial guarantees a successful outcome report. When designing the protocol, most researchers refer to electronic databases and extract protocol elements using a keyword search. However, state-of-the-art database systems only offer text-based searches for user-entered keywords. In this study, we present a database system with a context-dependent and protocol-element-selection function for successfully designing a clinical trial protocol. To do this, we first introduce a database for a protocol retrieval system constructed from individual protocol data extracted from 184,634 clinical trials and 13,210 frame structures of clinical trial protocols. The database contains a variety of semantic information that allows the filtering of protocols during the search operation. Based on the database, we developed a web application called the clinical trial protocol database system (CLIPS; available at https://corus.kaist.edu/clips). This system enables an interactive search by utilizing protocol elements. To enable an interactive search for combinations of protocol elements, CLIPS provides optional next element selection according to the previous element in the form of a connected tree. The validation results show that our method achieves better performance than that of existing databases in predicting phenotypic features.
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Affiliation(s)
- Junseok Park
- Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea
- Bio-Synergy Research Center, KAIST, Daejeon, Republic of Korea
| | - Seongkuk Park
- Information & Electronics Research Institute, Daejeon, Republic of Korea
| | - Kwangmin Kim
- Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea
- Bio-Synergy Research Center, KAIST, Daejeon, Republic of Korea
| | - Woochang Hwang
- The Milner Institute, University of Cambridge, Cambridge, United Kingdom
| | - Sunyong Yoo
- School of Electronics and Computer Engineering, Chonnam National University, Gwangju, Republic of Korea
| | - Gwan-su Yi
- Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea
- Bio-Synergy Research Center, KAIST, Daejeon, Republic of Korea
| | - Doheon Lee
- Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea
- Bio-Synergy Research Center, KAIST, Daejeon, Republic of Korea
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Stoppe C, Wendt S, Mehta NM, Compher C, Preiser JC, Heyland DK, Kristof AS. Biomarkers in critical care nutrition. Crit Care 2020; 24:499. [PMID: 32787899 PMCID: PMC7425162 DOI: 10.1186/s13054-020-03208-7] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 07/27/2020] [Indexed: 02/07/2023] Open
Abstract
The goal of nutrition support is to provide the substrates required to match the bioenergetic needs of the patient and promote the net synthesis of macromolecules required for the preservation of lean mass, organ function, and immunity. Contemporary observational studies have exposed the pervasive undernutrition of critically ill patients and its association with adverse clinical outcomes. The intuitive hypothesis is that optimization of nutrition delivery should improve ICU clinical outcomes. It is therefore surprising that multiple large randomized controlled trials have failed to demonstrate the clinical benefit of restoring or maximizing nutrient intake. This may be in part due to the absence of biological markers that identify patients who are most likely to benefit from nutrition interventions and that monitor the effects of nutrition support. Here, we discuss the need for practical risk stratification tools in critical care nutrition, a proposed rationale for targeted biomarker development, and potential approaches that can be adopted for biomarker identification and validation in the field.
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Affiliation(s)
- Christian Stoppe
- 3CARE—Cardiovascular Critical Care & Anesthesia Evaluation and Research, Aachen, Germany
- Department of Anesthesiology, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany
| | - Sebastian Wendt
- 3CARE—Cardiovascular Critical Care & Anesthesia Evaluation and Research, Aachen, Germany
| | - Nilesh M. Mehta
- Department of Anesthesiology, Critical Care and Pain Medicine, Division of Critical Care Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, MA USA
| | - Charlene Compher
- Department of Biobehavioral Health Science, University of Pennsylvania and Clinical Nutrition Support Service, Hospital of the University of Pennsylvania, Philadelphia, PA USA
| | - Jean-Charles Preiser
- Erasme University Hospital, Université Libre de Bruxelles, 808 route de Lennik, B-1070 Brussels, Belgium
| | - Daren K. Heyland
- Department of Critical Care Medicine, Queen’s University, Angada 4, Kingston, ON K7L 2V7 Canada
- Clinical Evaluation Research Unit, Kingston General Hospital, Angada 4, Kingston, ON K7L 2V7 Canada
| | - Arnold S. Kristof
- Meakins-Christie Laboratories and Translational Research in Respiratory Diseases Program, Faculty of Medicine, Departments of Medicine and Critical Care, Research Institute of the McGill University Health Centre, 1001 Décarie Blvd., EM3.2219, Montreal, QC H4A 3J1 Canada
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Madu CO, Wang S, Madu CO, Lu Y. Angiogenesis in Breast Cancer Progression, Diagnosis, and Treatment. J Cancer 2020; 11:4474-4494. [PMID: 32489466 PMCID: PMC7255381 DOI: 10.7150/jca.44313] [Citation(s) in RCA: 156] [Impact Index Per Article: 31.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Accepted: 04/04/2020] [Indexed: 02/07/2023] Open
Abstract
Angiogenesis is a significant event in a wide range of healthy and diseased conditions. This process frequently involves vasodilation and an increase in vascular permeability. Numerous players referred to as angiogenic factors, work in tandem to facilitate the outgrowth of endothelial cells (EC) and the consequent vascularity. Conversely, angiogenic factors could also feature in pathological conditions. Angiogenesis is a critical factor in the development of tumors and metastases in numerous cancers. An increased level of angiogenesis is associated with decreased survival in breast cancer patients. Therefore, a good understanding of the angiogenic mechanism holds a promise of providing effective treatments for breast cancer progression, thereby enhancing patients' survival. Disrupting the initiation and progression of this process by targeting angiogenic factors such as vascular endothelial growth factor (Vegf)-one of the most potent member of the VEGF family- or by targeting transcription factors, such as Hypoxia-Inducible Factors (HIFs) that act as angiogenic regulators, have been considered potential treatment options for several types of cancers. The objective of this review is to highlight the mechanism of angiogenesis in diseases, specifically its role in the progression of malignancy in breast cancer, as well as to highlight the undergoing research in the development of angiogenesis-targeting therapies.
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Affiliation(s)
- Chikezie O. Madu
- Departments of Biological Sciences, University of Memphis, Memphis, TN 38152. USA
| | - Stephanie Wang
- Departments of Biology and Advanced Placement Biology, White Station High School, Memphis, TN 38117. USA
| | - Chinua O. Madu
- Departments of Biology and Advanced Placement Biology, White Station High School, Memphis, TN 38117. USA
| | - Yi Lu
- Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, TN 38163. USA
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Serum RANKL levels and bioelectric impedance assessments in knee osteoarthritis patients. JOURNAL OF SURGERY AND MEDICINE 2020. [DOI: 10.28982/josam.697686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
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Lim WW, Leung NHL, Sullivan SG, Tchetgen Tchetgen EJ, Cowling BJ. Distinguishing Causation From Correlation in the Use of Correlates of Protection to Evaluate and Develop Influenza Vaccines. Am J Epidemiol 2020; 189:185-192. [PMID: 31598648 PMCID: PMC7217279 DOI: 10.1093/aje/kwz227] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Revised: 09/23/2019] [Accepted: 09/23/2019] [Indexed: 11/13/2022] Open
Abstract
There is increasing attention to the need to identify new immune markers for the evaluation of existing and new influenza vaccines. Immune markers that could predict individual protection against infection and disease, commonly called correlates of protection (CoPs), play an important role in vaccine development and licensing. Here, we discuss the epidemiologic considerations when evaluating immune markers as potential CoPs for influenza vaccines and emphasize the distinction between correlation and causation. While an immune marker that correlates well with protection from infection can be used as a predictor of vaccine efficacy, it should be distinguished from an immune marker that plays a mechanistic role in conferring protection against a clinical endpoint-the latter might be a more reliable predictor of vaccine efficacy and a more appropriate target for rational vaccine design. To clearly distinguish mechanistic and nonmechanistic CoPs, we suggest using the term "correlates of protection" for nonmechanistic CoPs, and ''mediators of protection'' for mechanistic CoPs. Furthermore, because the interactions among and relative importance of correlates or mediators of protection can vary according to age or prior vaccine experience, the effect sizes and thresholds for protective effects for CoPs could also vary in different segments of the population.
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Affiliation(s)
- Wey Wen Lim
- World Health Organization Collaborating Centre for Infectious Disease Epidemiology and Control, School of Public Health, the University of Hong Kong, Hong Kong SAR, People’s Republic of China
| | - Nancy H L Leung
- World Health Organization Collaborating Centre for Infectious Disease Epidemiology and Control, School of Public Health, the University of Hong Kong, Hong Kong SAR, People’s Republic of China
| | - Sheena G Sullivan
- World Health Organization Collaborating Centre for Reference and Research on Influenza at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
- Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, Los Angeles, California
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia
| | - Eric J Tchetgen Tchetgen
- Statistics Department, the Wharton School, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Benjamin J Cowling
- World Health Organization Collaborating Centre for Infectious Disease Epidemiology and Control, School of Public Health, the University of Hong Kong, Hong Kong SAR, People’s Republic of China
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Subtle Motor Signs as a Biomarker for Mindful Movement Intervention in Children with Attention-Deficit/Hyperactivity Disorder. J Dev Behav Pediatr 2020; 41:349-358. [PMID: 32555070 PMCID: PMC7554196 DOI: 10.1097/dbp.0000000000000795] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
OBJECTIVE Previous studies of Tai Chi or mindfulness-based interventions in attention-deficit/hyperactivity disorder (ADHD) have relied on self- or parent-reported outcome measures; however, there is a critical need for the validation of objective biomarkers of treatment. Therefore, we implemented a mindful movement intervention for children with ADHD, hypothesizing that an ADHD-relevant motor control measure could serve as a predictive biomarker of treatment-related improvement. METHODS Thirty-four participants were included, 8 to 12 year olds diagnosed with DSM-5 ADHD. Participants engaged in the mindful movement treatment, an 8-week program with 2 classes a week for 60 minutes. At pre- and post-treatment, ADHD symptoms and associated impairment and motor control via the Physical and Neurological Examination for Subtle Signs (PANESS) were assessed. RESULTS The results showed a significant reduction for PANESS Gaits and Station (p ≤ 0.001), total overflow (p = 0.009), and total score (p = 0.001) after treatment, with the largest effect for Gaits and Stations. The results also showed a significant reduction in symptoms of inattention (p ≤ 0.001), hyperactivity/impulsivity (p ≤ 0.001), oppositional defiant disorder (p = 0.001), and executive dysfunction (p ≤ 0.001). There were significant positive correlations between change in PANESS Gaits and Stations and change in both inattentive (p = 0.02) and hyperactive/impulsive symptoms (p = 0.02). There was also a significant positive correlation between change in the PANESS total score and change in inattentive (p = 0.007) and hyperactive/impulsive symptoms (p = 0.042). The change in the PANESS total score (β = 0.295, p = 0.002) predicted post-treatment ADHD severity above the change in inattentive or hyperactive/impulsive symptoms. CONCLUSION The results suggest the effectiveness of a mindful movement treatment on ADHD symptoms and suggest the PANESS as a candidate motor biomarker for future mindful movement trials. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov, NCT02234557, https://clinicaltrials.gov/ct2/show/NCT02234557.
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Dharmadhikari AS, Jaiswal SV, Tandle AL, Sinha D, Jog N. Study of Frontal Alpha Asymmetry in Mild Depression: A Potential Biomarker or Not? J Neurosci Rural Pract 2019; 10:250-255. [PMID: 31001013 PMCID: PMC6454961 DOI: 10.4103/jnrp.jnrp_293_18] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Background: Depression, despite being the most common of mental illness lacks any quantifiable and absolute biomarker. Frontal alpha asymmetry (FAA) is proposed as biomarker of depression both in resting and activated state. Yet, the location of extraction of alpha, clinical utility as well as validity of FAA is uncertain. With aim of obtaining clarity on this confusion we conducted this study. Methodology: Electroencephalographic frontal alpha power was calculated in patients of depression (n = 24) and compared with healthy controls (n = 17) for the assessment of FAA. Both groups were studied for resting phase and activation phase changes in FAA. For activation phase, auditory stimuli in the form of Indian classical music were used. Results: Frontal alpha power was measured across FP1, FP2, F3, F4, F7, and F8. Mean powers were compared in resting (before), activated (during) and postactivated resting stage (after). FAA was statistically significant in F7–F8 pair of electrodes and on F7 electrode when compared between cases and controls. Conclusion: Quest for biomarker for depression churned out FAA as frontrunner. Despite of vast amount of research on it, practical utility eludes us. We need to revisit our approach from conventional search of the diagnostic biomarker; as FAA might reflect component of depression but not totally disorder. In our opinion, we are not yet ready for it and have a road ahead to travel.
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Affiliation(s)
- Ambrish S Dharmadhikari
- Department of Psychiatry, H. B. T. Medical College and Dr. R. N. Cooper Mun. Gen. Hospital, Mumbai, Maharashtra, India
| | - Suyog Vijay Jaiswal
- Department of Psychiatry, H. B. T. Medical College and Dr. R. N. Cooper Mun. Gen. Hospital, Mumbai, Maharashtra, India
| | - Avinash L Tandle
- Department of Electronics and Telecommunication, Mukesh Patel School of Technology, Management and Engineering, NMIMS University, Mumbai, Maharashtra, India
| | - Deoraj Sinha
- Department of Psychiatry, H. B. T. Medical College and Dr. R. N. Cooper Mun. Gen. Hospital, Mumbai, Maharashtra, India
| | - Nandini Jog
- Department of Electronics and Telecommunication, Mukesh Patel School of Technology, Management and Engineering, NMIMS University, Mumbai, Maharashtra, India
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Olshansky B. Can’t get out of this world alive. Europace 2019; 21:995-996. [DOI: 10.1093/europace/euz063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023] Open
Affiliation(s)
- Brian Olshansky
- Department of Internal Medicine, University of Iowa 200 Hawkins Drive, Iowa City, IA, USA
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Allen PI, Conzemius MG, Evans RB, Kiefer K. Correlation between synovial fluid cytokine concentrations and limb function in normal dogs and in dogs with lameness from spontaneous osteoarthritis. Vet Surg 2019; 48:770-779. [PMID: 31032990 DOI: 10.1111/vsu.13212] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Revised: 05/22/2018] [Accepted: 07/18/2018] [Indexed: 12/14/2022]
Abstract
OBJECTIVE To determine the relationship between synovial biomarker concentrations and severity of lameness and to assess the ability to differentiate normal from osteoarthritic joints with synovial biomarker concentrations. STUDY DESIGN Prospective clinical study. SAMPLE POPULATION Twelve hounds with no evidence of osteoarthritis (OA) and 27 client-owned dogs with unilateral lameness and joint pain in a single joint from naturally occurring OA. METHODS Enrollment in the OA group required a history of lameness, radiographic evidence of OA on orthogonal joint radiographs, and ≥6% gait asymmetry between contralateral limbs. The concentrations of 14 synovial OA biomarkers in synovial samples obtained after gait analysis were measured with enzyme-linked immunosorbent assays and compared between normal and OA joints. RESULTS Concentrations of monocyte chemoattractant protein (MCP)-1, substance P, interleukin (IL)-6, IL-8, KC-like, matrix metalloproteinase (MMP)-1, and MMP-3 were greater (P ≤ .05) in OA than in normal joints. The concentrations of bradykinin and tissue inhibitors of metalloproteinase-4 were decreased in OA compared with normal joints. Monocyte chemoattractant protein 1 was identified as the most accurate marker to distinguish OA from normal joints. No correlation was detected between any OA biomarker concentration, individually or in combination, and severity of gait asymmetry at the walk. CONCLUSION Differences in proinflammatory and anti-inflammatory biomarkers were detected between OA and normal joints, but no relationship was identified between biomarker concentrations and gait asymmetry in dogs with OA. CLINICAL IMPACT This information will help guide future studies to elucidate how factors such as disease chronicity, severity, and etiology affect these relationships.
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Affiliation(s)
- Philip I Allen
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, Minnesota
| | - Michael G Conzemius
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, Minnesota
| | - Richard B Evans
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, Minnesota
| | - Kristina Kiefer
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, Minnesota
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Affiliation(s)
- Randi Foraker
- Institute for Informatics, Washington University School of Medicine, St. Louis, Missouri
| | - Douglas L Mann
- Center for Cardiovascular Research, Cardiovascular Division, Washington University School of Medicine, St. Louis, Missouri
| | - Philip R O Payne
- Institute for Informatics, Washington University School of Medicine, St. Louis, Missouri
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Machado SC, Martins I. Risk assessment of occupational pesticide exposure: Use of endpoints and surrogates. Regul Toxicol Pharmacol 2018; 98:276-283. [DOI: 10.1016/j.yrtph.2018.08.008] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Revised: 07/20/2018] [Accepted: 08/16/2018] [Indexed: 10/28/2022]
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Stamp L, Morillon MB, Taylor WJ, Dalbeth N, Singh JA, Lassere M, Christensen R. Serum urate as surrogate endpoint for flares in people with gout: A systematic review and meta-regression analysis. Semin Arthritis Rheum 2018; 48:293-301. [PMID: 29566967 DOI: 10.1016/j.semarthrit.2018.02.009] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2017] [Revised: 01/17/2018] [Accepted: 02/16/2018] [Indexed: 01/22/2023]
Abstract
OBJECTIVES The primary efficacy outcome in trials of urate lowering therapy (ULT) for gout is serum urate (SU). The aim of this study was to examine the strength of the relationship between SU and patient-important outcomes to determine whether SU is an adequate surrogate endpoint for clinical trials. METHODS Multiple databases through October 2017 were searched. Randomized controlled trials comparing any ULT in people with gout with any control or placebo, ≥three months duration were included. Open label extension (OLE) trial data were included in secondary analyses. Standardized data elements were extracted independently by two reviewers. RESULTS Ten RCTs and 3 OLE studies were identified. From the RCTs (maximum duration 24 months) meta-regression did not reveal an association between the relative risk of a gout flare and the difference in proportions of individuals with SU < 6mg/dL (P = 0.47; R2 = 8%). In a post hoc analysis, the ratio of the time in months at which the proportion of individuals having a flare was reported/time in months at which the proportion of individuals with SU < 6mg/dL was reported was calculated and studies where the ratio was <2 were excluded. Using the remaining 6 studies there was an association between proportion of individuals achieving SU < 6mg/dL and gout flares (over patient years). Duration of ULT was inversely associated with the proportion of patients experiencing a flare. Study duration and variability in reporting of outcomes limited the analysis. Observational studies supported the trend of fewer flares in those with lower SU. CONCLUSIONS Based on aggregate clinical trial-level data an association between SU and gout flare could not be confirmed. However, based on observational ecological study design data-including longer duration extension studies-SU < 6mg/dL was associated with reduced gout flares.
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Affiliation(s)
- Lisa Stamp
- Department of Medicine, University of Otago, Christchurch, P.O. Box 4345, Christchurch, New Zealand.
| | - Melanie B Morillon
- Musculoskeletal Statistics Unit, The Parker Institute, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark; Department of Rheumatology, Odense University Hospital, Denmark; Department of Medicine, Vejle Hospital, Denmark
| | - William J Taylor
- Department of Medicine, University of Otago, Wellington, New Zealand
| | - Nicola Dalbeth
- Department of Medicine, University of Auckland, New Zealand
| | - Jasvinder A Singh
- Department of Medicine, University of Alabama at Birmingham & Birmingham Veterans Affairs Medical Center, Birmingham, Alabama
| | - Marissa Lassere
- Department of Rheumatology, St George Hospital, University of NSW, Sydney, Australia
| | - Robin Christensen
- Musculoskeletal Statistics Unit, The Parker Institute, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark
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Pengas I, Eldridge S, Assiotis A, McNicholas M, Mendes JE, Laver L. MMP-3 in the peripheral serum as a biomarker of knee osteoarthritis, 40 years after open total knee meniscectomy. J Exp Orthop 2018; 5:21. [PMID: 29904905 PMCID: PMC6003895 DOI: 10.1186/s40634-018-0132-x] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Accepted: 05/17/2018] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND To explore potential biomarkers in a meniscectomy-induced knee osteoarthritis model, at forty years after meniscectomy. METHODS We carried out a forty-year study of 53 patients who, as adolescents, underwent open total meniscectomy and assessed two potential synovial and serum biomarkers, namely glycosaminoglycan (GAG) and matrix metalloproteinase-3 (MMP-3). Of the 30 patients available for review, 8 had contralateral knee operations and were excluded. Of the remaining 22 patients, 17 had successful operated knee synovial fluid aspirations and 8 also had successful contralateral control knee aspirations. GAG and MMP3 levels in the synovial fluid and peripheral serum was measured using Alcian blue precipitation and ELISA quantification, respectively. Patients also had their knee radiographs assessed and their radiographic osteoarthritis classified as per the Kellgren-Lawrence and Ahlbӓck systems. RESULTS At forty years after meniscectomy, synovial MMP-3 levels remain increased (p = 0.0132) while GAG levels were reduced (p = 0.0487) when compared to controls and these two levels correlate inversely. Furthermore, levels of synovial MMP-3 significantly correlated (p = 0.0032, r = 0.7734; p = 0.0256, r = 0.5552) and GAG levels significantly inversely correlated (p = 0.0308, r = - 0.6220; p = 0.0135, r = - 0.6024), respectively, with both radiological scoring systems. Interestingly, we found that the levels of serum MMP-3 correlated only with the synovial fluid levels of MMP-3 in the operated knee and not with the non-operated joint (p = 0.0252, r = 0.7706 vs. p = 0.0764, r = 0.6576). Multiple regression analysis for patient's quality of life based on these biomarkers revealed an almost perfect result with an R2 of 0.9998 and a p value = 0.0087. CONCLUSION Our results suggest that serum levels of MMP3 could be used as a potential biomarker for knee osteoarthritis, using a simple blood test. Larger cohorts are desirable in order to prove or disprove this finding.
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Affiliation(s)
- Ioannis Pengas
- Consultant Trauma & Orthopaedic Knee Surgeon, Joint Preservation & Soft Tissue Knee Specialist, Royal Cornwall Teaching Hospitals NHS Trust Treliske, Truro, TR1 3LQ, UK.
| | - Suzanne Eldridge
- Department of Experimental Medicine and Rheumatology, William Harvey Research Institute. Barts and The London, Queen Mary's School of Medicine and Dentistry, London, EC1M 6BQ, UK
| | - Aggelos Assiotis
- Specialist registrar in Trauma & Orthopaedics, Chelsea & Westminster Hospital NHS Foundation Trust, 369 Fulham Rd, Chelsea, London, SW10 9NH, UK
| | - Michael McNicholas
- Consultant Trauma & Orthopaedic Knee Surgeon, Aintree University Hospital NHS Foundation Trust Longmoor Ln, Liverpool, L9 7AL, UK
| | - Joao Espregueira Mendes
- Orthopaedics Department of Minho University, R. da Universidade, Minho University, 4710-057, Braga, Portugal
| | - Lior Laver
- Department of Arthroscopy, The Royal Orthopaedic Hospital, The Woodlands, Bristol Rd S, Birmingham, B31 2AP, UK
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Affiliation(s)
- Timothy E. Yap
- Imperial College Healthcare NHS Trust (ICHNT), The Western Eye Hospital, London, UK
- The Imperial College Ophthalmic Research Group (ICORG), Imperial College London, London, UK
| | - Eduardo M. Normando
- Imperial College Healthcare NHS Trust (ICHNT), The Western Eye Hospital, London, UK
- The Imperial College Ophthalmic Research Group (ICORG), Imperial College London, London, UK
| | - Maria Francesca Cordeiro
- Imperial College Healthcare NHS Trust (ICHNT), The Western Eye Hospital, London, UK
- The Imperial College Ophthalmic Research Group (ICORG), Imperial College London, London, UK
- Department of Visual Neuroscience, Glaucoma and Retinal Neurodegeneration Group, UCL Institute of Ophthalmology, London, UK
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Desmosine and Isodesmosine as a Novel Biomarker for Pulmonary Arterial Hypertension: A Pilot Study. Am J Ther 2018; 24:e399-e404. [PMID: 26237301 DOI: 10.1097/mjt.0000000000000260] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Delayed diagnosis is common in patients with pulmonary arterial hypertension (PAH). Right-sided heart catheterization, the gold standard for diagnosis, is invasive and cannot be applied for routine screening. Some biomarkers have been looked into; however, due to the lack of a clear pathological mechanism linking the marker to PAH, the search for an ideal one is still ongoing. Elastin is a significant structural constituent of blood vessels. Its synthesis involves cross-linking of monomers by 2 amino acids, desmosine and isodesmosine (D&I). Being extremely stable, elastin undergoes little metabolic turnover in healthy individuals resulting in very low levels of D&I amino acids in the human plasma, urine, or sputum. We hypothesized that in PAH patients, the elastin turnover is high; which in turn should result in elevated levels of D&I in plasma and urine. Using mass spectrometry, plasma and urine levels of D&I were measured in 20 consecutive patients with PAH confirmed by cardiac catheterization. The levels were compared with 13 healthy controls. The mean level of total plasma D&I in patients with PAH was 0.47 ng/mL and in controls was 0.19 ng/mL (P = 0.001). The mean levels of total D&I in the urine of PAH patients was 20.55 mg/g creatinine and in controls was 12.78 mg/g creatinine (P = 0.005). The mean level of free D&I in the urine of PAH patients was 10.34 mg/g creatinine and in controls was 2.52 mg/g creatinine (P < 0.001). This is the first study highlighting that the serum and urine D&I has a potential to be a novel screening biomarker for patients with PAH. It paves the way for larger studies to analyze its role in assessing for disease severity and response to treatment.
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