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Journal of Internal Medicine Oct 2020
Topics: Biomarkers; Cardiovascular Diseases; Coronary Disease; Humans; Lysine; Methylamines; Myocardial Infarction; Oxides; Virulence Factors
PubMed: 32424985
DOI: 10.1111/joim.13086 -
International Journal of Surgery... Oct 2020Hepatocellular carcinoma (HCC) is the liver's most common primary malignancy, with over half a million new cases diagnosed each year and being the fourth leading cause... (Review)
Review
Hepatocellular carcinoma (HCC) is the liver's most common primary malignancy, with over half a million new cases diagnosed each year and being the fourth leading cause of cancer death, worldwide. The poor prognosis of HCC is largely related to late diagnosis. Historically, serum alpha-fetoprotein and diagnostic imaging have been primary diagnostic modalities. However, the poor prognosis due to late diagnosis of HCC has proven unacceptable and, recently, significant efforts have been devoted to identifying patients with early stage HCC. Molecular biomarkers can provide additional and relevant information about the biological behavior of these tumors. Research in biomarker combinations may provide more accurate and valuable information for the future individualized HCC diagnosis and/or prognosis. Several biomarkers with prognostic significance have been identified, however all of them have been studied retrospectively. Furthermore, of all different molecular signatures that have been published, very few have been externally validated. The aim of this review is to analyze the most relevant emerging biomarkers of HCC.
Topics: Biomarkers, Tumor; Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Predictive Value of Tests; Prognosis; Reference Values; Retrospective Studies; Sensitivity and Specificity; Severity of Illness Index
PubMed: 32344023
DOI: 10.1016/j.ijsu.2020.04.043 -
Parkinsonism & Related Disorders Jan 2014There is a pressing need for biomarkers to diagnose Parkinson's disease (PD), assess disease severity, and prognosticate course. Various types of biologic specimens are... (Review)
Review
There is a pressing need for biomarkers to diagnose Parkinson's disease (PD), assess disease severity, and prognosticate course. Various types of biologic specimens are potential candidates for identifying biomarkers--defined here as surrogate indicators of physiological or pathophysiological states--but blood has the advantage of being minimally invasive to obtain. There are, however, several challenges to identifying biomarkers in blood. Several candidate biomarkers identified in other diseases or in other types of biological fluids are being pursued as blood-based biomarkers in PD. In addition, unbiased discovery is underway using techniques including metabolomics, proteomics, and gene expression profiling. In this review, we summarize these techniques and discuss the challenges and successes of blood-based biomarker discovery in PD. Blood-based biomarkers that are discussed include α-synuclein, DJ-1, uric acid, epidermal growth factor, apolipoprotein-A1, and peripheral inflammatory markers.
Topics: Biomarkers; Humans; Parkinson Disease
PubMed: 24262199
DOI: 10.1016/S1353-8020(13)70025-7 -
Archivos de Cardiologia de Mexico 2023This review summarizes the impact of gender affirming hormone therapy used in the transgendered population and the classic and emerging risk factors on cardiovascular... (Review)
Review
This review summarizes the impact of gender affirming hormone therapy used in the transgendered population and the classic and emerging risk factors on cardiovascular outcomes and surrogate markers of cardiovascular health. There is a growing body of evidence that people who are transgender and gender diverse are impacted by disparities across a variety of cardiovascular risk factors compared with their peers who are cisgender. Previously, disparities have been reported in cardiovascular morbidity and mortality across this group as a result of a higher prevalence of non-healthy life style. However, recent research suggests that there are additional factors playing a role in this differences: there is the hypothesis that the excess of cardiovascular morbility and mortality has been driven by psychosocial stressors across the lifespan at multiple levels, as structural violence (e.g., discrimination, lack of affordable housing, lack of access to health care, etc.). Lack of information and research in this population is an important limitation; therefore, a multifaceted approach that integrates best practice into research, health promotion and cardiovascular care for this understudied and growing population is clearly needed.
Topics: Humans; Transgender Persons; Cardiovascular Diseases; Risk Factors; Biomarkers
PubMed: 37992700
DOI: 10.24875/ACM.M23000091 -
Clinical Trials (London, England) Aug 2015A surrogate marker is a variable commonly used in clinical trials to guide treatment decisions when the outcome of ultimate interest is not available. A good surrogate...
BACKGROUND
A surrogate marker is a variable commonly used in clinical trials to guide treatment decisions when the outcome of ultimate interest is not available. A good surrogate marker is one where the treatment effect on the surrogate is a strong predictor of the effect of treatment on the outcome. We review the situation when there is one treatment delivered at baseline, one surrogate measured at one later time point, and one ultimate outcome of interest and discuss new issues arising when variables are time-varying.
METHODS
Most of the literature on surrogate markers has only considered simple settings with one treatment, one surrogate, and one outcome of interest at a fixed time point. However, more complicated time-varying settings are common in practice. In this article, we describe the unique challenges in two settings, time-varying treatments and time-varying surrogates, while relating the ideas back to the causal-effects and causal-association paradigms.
CONCLUSION
In addition to discussing and extending popular notions of surrogacy to time-varying settings, we give examples illustrating that one can be misled by not taking into account time-varying information about the surrogate or treatment. We hope this article has provided some motivation for future work on estimation and inference in such settings.
Topics: Biomarkers; Clinical Trials as Topic; Humans; Mathematical Concepts; Outcome Assessment, Health Care; Regression Analysis; Therapeutics; Time Factors
PubMed: 25948621
DOI: 10.1177/1740774515583500 -
Liver International : Official Journal... Sep 2021Non-alcoholic steatohepatitis has emerged as a major public health problem, and the burden of non-alcoholic steatohepatitis cirrhosis is projected to increase by... (Review)
Review
Non-alcoholic steatohepatitis has emerged as a major public health problem, and the burden of non-alcoholic steatohepatitis cirrhosis is projected to increase by 64%-156% by 2030. The threat is aggravated by the fact that are currently no approved drugs for the treatment of non-alcoholic steatohepatitis. In this paper, we review the main challenges to drug development in patients with non-alcoholic steatohepatitis cirrhosis, and describe the opportunities brought by the advances in the understanding of the clinical and pathophysiological nuances of cirrhosis. The design of therapeutic regimens for non-alcoholic steatohepatitis cirrhosis will vary according to the specific cirrhosis substage (compensated vs decompensated), and the specific mechanistic basis of therapy, targeted either at improving aetiology-specific pathways and/or at more general aetiology-agnostic processes. The understanding of the probabilistic expectations for the whole range of potential outcomes, rooted at different mechanistic drivers at each specific substage, will be essential in order to choose adequate estimands and therapeutic strategies for clinical trials and individual patients with non-alcoholic steatohepatitis cirrhosis. Finally, we provide a summary of the main pitfalls and uncertainties in the design of clinical trials for non-alcoholic steatohepatitis cirrhosis and discuss potential biomarkers for use in trials and practice for these patients.
Topics: Biomarkers; Humans; Liver Cirrhosis; Non-alcoholic Fatty Liver Disease
PubMed: 34242466
DOI: 10.1111/liv.15013 -
Biostatistics (Oxford, England) Oct 2023When evaluating the effectiveness of a treatment, policy, or intervention, the desired measure of efficacy may be expensive to collect, not routinely available, or may... (Randomized Controlled Trial)
Randomized Controlled Trial
When evaluating the effectiveness of a treatment, policy, or intervention, the desired measure of efficacy may be expensive to collect, not routinely available, or may take a long time to occur. In these cases, it is sometimes possible to identify a surrogate outcome that can more easily, quickly, or cheaply capture the effect of interest. Theory and methods for evaluating the strength of surrogate markers have been well studied in the context of a single surrogate marker measured in the course of a randomized clinical study. However, methods are lacking for quantifying the utility of surrogate markers when the dimension of the surrogate grows. We propose a robust and efficient method for evaluating a set of surrogate markers that may be high-dimensional. Our method does not require treatment to be randomized and may be used in observational studies. Our approach draws on a connection between quantifying the utility of a surrogate marker and the most fundamental tools of causal inference-namely, methods for robust estimation of the average treatment effect. This connection facilitates the use of modern methods for estimating treatment effects, using machine learning to estimate nuisance functions and relaxing the dependence on model specification. We demonstrate that our proposed approach performs well, demonstrate connections between our approach and certain mediation effects, and illustrate it by evaluating whether gene expression can be used as a surrogate for immune activation in an Ebola study.
Topics: Humans; Models, Statistical; Biomarkers; Causality; Computer Simulation
PubMed: 35791753
DOI: 10.1093/biostatistics/kxac020 -
NeuroRx : the Journal of the American... Apr 2004Interest is increasing rapidly in the use of surrogate markers as primary measures of the effectiveness of investigational drugs in definitive drug trials. Many such... (Review)
Review
Interest is increasing rapidly in the use of surrogate markers as primary measures of the effectiveness of investigational drugs in definitive drug trials. Many such surrogate markers have been proposed as potential candidates for use in definitive effectiveness trials of agents to treat neurologic or psychiatric disease, but as of this date, there are no such markers that have been adequately "validated," that is, shown to predict the effect of the treatment on the clinical outcome of interest. While the current law and regulations permit the United States Food and Drug Administration to base the approval of a drug product on a determination the effect of the drug on an unvalidated surrogate marker (that is, one for which it is not known that an effect on the surrogate actually predicts the desired clinical benefit), there are a number of difficulties in interpreting trials that use surrogate markers as primary measures of drug effect. In this article, the relevant regulatory context will be discussed, as well as the epistemological problems related to the interpretation of clinical trials in which unvalidated surrogate markers are used as primary outcomes.
Topics: Biomarkers; Clinical Trials as Topic; Humans; United States; United States Food and Drug Administration
PubMed: 15717019
DOI: 10.1602/neurorx.1.2.189 -
Ageing Research Reviews May 2017The first clinical trial aimed at targeting fundamental processes of aging will soon be launched (TAME: Targeting Aging with Metformin). In its wake is a robust pipeline... (Review)
Review
The first clinical trial aimed at targeting fundamental processes of aging will soon be launched (TAME: Targeting Aging with Metformin). In its wake is a robust pipeline of therapeutic interventions that have been demonstrated to extend lifespan or healthspan of preclinical models, including rapalogs, antioxidants, anti-inflammatory agents, and senolytics. This ensures that if the TAME trial is successful, numerous additional clinical trials are apt to follow. But a significant impediment to these trials remains the question of what endpoints should be measured? The design of the TAME trial very cleverly skirts around this based on the fact that there are decades of data on metformin in humans, providing unequaled clarity of what endpoints are most likely to yield a positive outcome. But for a new chemical entity, knowing what endpoints to measure remains a formidable challenge. For economy's sake, and to achieve results in a reasonable time frame, surrogate markers of lifespan and healthy aging are desperately needed. This review provides a comprehensive analysis of molecular endpoints that are currently being used as indices of age-related phenomena (e.g., morbidity, frailty, mortality) and proposes an approach for validating and prioritizing these endpoints.
Topics: Aging; Biomarkers; Humans; Life Expectancy; Longevity; Pathology, Molecular
PubMed: 27721062
DOI: 10.1016/j.arr.2016.09.012 -
Therapeutic Advances in Cardiovascular... Oct 2011Although low-density lipoprotein cholesterol (LDL-C) lowering represents the mainstay of current lipid treatment, high-density lipoprotein cholesterol (HDL-C) has... (Review)
Review
Although low-density lipoprotein cholesterol (LDL-C) lowering represents the mainstay of current lipid treatment, high-density lipoprotein cholesterol (HDL-C) has generated increasing interest as a secondary therapeutic target because of strong evidence that serum HDL-C concentration is inversely associated with coronary heart disease risk. Niacin is a lipid-altering drug that has been used to lower cholesterol since the 1950s. In addition to its LDL-C-lowering effects, niacin is the most effective agent currently available for raising HDL-C. Despite its long history as a lipid-altering drug, only limited data are available regarding its clinical benefit alone and in combination with other agents, and the majority of studies investigating its impact on clinical outcomes are from the pre-statin area. Several studies have demonstrated a beneficial effect of treatment with niacin in combination with statin therapy on surrogate cardiovascular markers (e.g. carotid intima-media thickness). However, the clinical significance of these surrogate markers has been questioned. Two large randomized trials will address whether niacin-statin combination therapy is an appropriate therapeutic alternative to statin monotherapy.
Topics: Biomarkers; Cardiovascular Diseases; Cholesterol, HDL; Cholesterol, LDL; Drug Therapy, Combination; Dyslipidemias; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Niacin; Risk Factors
PubMed: 21893559
DOI: 10.1177/1753944711419197