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Biometrics Jun 2021The use of surrogate markers to examine the effectiveness of a treatment has the potential to decrease study length and identify effective treatments more quickly. Most...
The use of surrogate markers to examine the effectiveness of a treatment has the potential to decrease study length and identify effective treatments more quickly. Most available methods to investigate the usefulness of a surrogate marker involve restrictive parametric assumptions and tend to focus on settings where the surrogate is measured at a single point in time. However, in many clinical settings, the potential surrogate marker is often measured repeatedly over time, and thus, the surrogate marker information is a trajectory of measurements. In addition, it is often difficult in practice to correctly specify the relationship between a treatment, primary outcome, and surrogate marker trajectory. In this paper, we propose a model-free definition for the proportion of the treatment effect on the primary outcome that is explained by the treatment effect on the longitudinal surrogate markers. We propose three novel flexible methods to estimate this proportion, develop the asymptotic properties of our estimators, and investigate the robustness of the estimators under multiple settings via a simulation study. We apply our proposed procedures to an AIDS clinical trial dataset to examine a trajectory of CD4 counts as a potential surrogate.
Topics: Biomarkers; Computer Simulation; Treatment Outcome
PubMed: 32506496
DOI: 10.1111/biom.13310 -
BioMed Research International 2021Several decades of improving dairy cattle towards unilateral utilization of dairy cattle led to enormous progress in the field of milk yield; however, it resulted in a... (Review)
Review
Several decades of improving dairy cattle towards unilateral utilization of dairy cattle led to enormous progress in the field of milk yield; however, it resulted in a number of unfavorable features, such as reproductive disorders, increased calf mortality, and reduced health. Most cases of embryo loss and/or lost pregnancies occur during the first four to five weeks of gestation; accurate detection for pregnancy during this period is likely to contribute to an improvement in gestation rates. A specific protein, interferon-tau (IFNT), stimulates interferon-stimulated genes (ISGs), and their expression increases during gestation within 21 days after insemination. In bovines, the early conceptus undergoes a phase of rapid growth and elongation before implantation, the latter occurring 2-3 weeks after fertilization. IFNT acts mainly in the endometrium of the luminal epithelium. It is a new type I interferon that regulates several genes encoding uterine-derived factors. They are crucial in the processes of preparing the uterus for placenta attachment, modifying the uterine immune system, and regulating early fetal development. Because IFNT is expressed and induces ISGs in the endometrium during pregnancy recognition, it was reasoned that surrogate markers for pregnancy or IFNT might be present in the blood and provide an indicator of pregnancy status in cattle.
Topics: Animals; Biomarkers; Cattle; Embryo, Mammalian; Endometrium; Epithelium; Female; Gene Expression; Gene Expression Regulation; Interferon Type I; Pregnancy; Pregnancy Proteins; Uterus
PubMed: 34513997
DOI: 10.1155/2021/9915814 -
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 -
Seminars in Arthritis and Rheumatism Oct 1995The joint destruction of osteoarthritis (OA) comprises loss of articular cartilage resulting from an imbalance of enzyme-catalized cartilage breakdown and regeneration.... (Review)
Review
The joint destruction of osteoarthritis (OA) comprises loss of articular cartilage resulting from an imbalance of enzyme-catalized cartilage breakdown and regeneration. OA is thought to derive from defective chondrocyte metabolism and thus to inherently lack the large-scale systemic response that is the hallmark of rheumatoid arthritis (RA). Because of the apparent absence of systemic inflammation in OA, acute-phase response proteins have not been as extensively studied in OA as they have been in RA. The diagnosis of OA almost always involves radiographic assessment of joint damage, which is useful only after the disease process has been underway for several months. Radiographic evaluation cannot give a good assessment of current disease activity and is a relatively insensitive indicator of prognosis. Cartilage breakdown products can potentially serve as direct surrogate markers of OA disease activity, but have not been extensively used because of their limited sensitivity and the technical difficulties associated with their measurement. Markers of disease activity in RA are indirect and are derived from the acute-phase response, a cycle of temporal changes in cellular and metabolic function. The early part of the acute-phase response involves the local action and production of cytokines such as interleukin-1 (IL-1), tumor necrosis factor (TNF-alpha) and IL-6. In the late acute-phase response, these cytokines can effect many systemic changes, including increased production of acute-phase proteins (APP). Three valuable surrogate markers of disease activity in RA are provided by the acute-phase response: the time-honored erythrocyte sedimentation rate (ESR) and the newer APPs C-reactive protein (CRP) and serum amyloid A (SAA). As in RA, the joint destruction of OA involves IL-1, TNF-alpha, and IL-6; however, OA can be viewed as an indolent stimulus of the later (systemic) acute-phase response. Recent studies of the acute-phase response in OA suggest that the concentrations of CRP and SAA are elevated in OA, but to a lesser extent than in RA. In the future, long-term monitoring of CRP concentrations in the blood may permit the earlier detection and more effective treatment of OA.
Topics: Acute-Phase Proteins; Biomarkers; Blood Sedimentation; C-Reactive Protein; Cytokines; Humans; Osteoarthritis; Serum Amyloid A Protein; Synovial Fluid; Time Factors
PubMed: 8578314
DOI: 10.1016/s0049-0172(95)80020-4 -
Clinical Nutrition (Edinburgh, Scotland) Dec 2022Low muscle mass is a common condition in the critically ill population and is associated with adverse clinical outcomes. The primary aim of this study was to analyze the...
INTRODUCTION
Low muscle mass is a common condition in the critically ill population and is associated with adverse clinical outcomes. The primary aim of this study was to analyze the prognostic significance of low muscle mass using computed tomography (CT) scans in COVID-19 critically ill patients. A second objective was to determine the accuracy and agreement in low muscle mass identification using diverse markers compared to CT as the gold standard.
METHODS
This was a prospective cohort study of COVID-19 critically ill patients. Skeletal muscle area at the third lumbar vertebra was measured. Clinical outcomes (intensive care unit [ICU] and hospital length of stay [LOS], tracheostomy, days on mechanical ventilation [MV], and in-hospital mortality) were assessed. Phase angle, estimated fat-free mass index, calf circumference, and mid-upper arm circumference were measured as surrogate markers of muscle mass.
RESULTS
Eighty-six patients were included (mean age ± SD: 48.6 ± 12.9; 74% males). Patients with low muscle mass (48%) had a higher rate of tracheostomy (50 vs 20%, p = 0.01), prolonged ICU (adjusted HR 0.53, 95%CI 0.30-0.92, p = 0.024) and hospital LOS (adjusted HR 0.50, 95% CI 0.29-0.86, p = 0.014). Bedside markers of muscle mass showed poor to fair agreement and accuracy compared to CT-assessed low muscle mass.
CONCLUSION
Low muscle mass at admission was associated with prolonged length of ICU and hospital stays. Further studies are needed to establish targeted nutritional interventions to halt and correct the catabolic impact of COVID-19 in critically ill patients, based on standardized and reliable measurements of body composition.
Topics: Male; Humans; Female; Critical Illness; Prognosis; COVID-19; Prospective Studies; Intensive Care Units; Length of Stay; Muscle, Skeletal; Biomarkers
PubMed: 35282986
DOI: 10.1016/j.clnu.2022.02.019 -
Journal of Diabetes Investigation Mar 2018The present study evaluated the ability of lipid accumulation product (LAP), visceral adiposity index (VAI), and the product of triglycerides and glucose (TyG), three...
AIMS/INTRODUCTION
The present study evaluated the ability of lipid accumulation product (LAP), visceral adiposity index (VAI), and the product of triglycerides and glucose (TyG), three novel markers, in identifying metabolic syndrome (MetS) with different criteria in middle-aged and elderly Chinese.
MATERIALS AND METHODS
During June 2012 to January 2013, 992 consecutive patients (age ≥40 years) were enrolled at Daping Hospital. The criteria of MetS were based on the International Diabetes Federation and the modified National Cholesterol Education Program's Adult Treatment Panel III. VAI, LAP and TyG were computed based on a published mathematical model.
RESULTS
The prevalence of MetS was 42.8%. The receiver operating characteristic curve found LAP, VAI and TyG were positively related to MetS in both criteria. The optimal cut-offs of VAI, LAP and TyG for the modified National Cholesterol Education Program's Adult Treatment Panel III and International Diabetes Federation criteria were 2.015, 31.465 and 8.706, and 2.035, 37.99 and 8.697, respectively. After adjustment of potential confounding factors, VAI, LAP and TyG were significantly correlated with MetS in all criteria according to optimal cut-offs. For MetS, reliable predictive value was observed in different subgroups (age and sex). LAP showed the greatest area under the curve in MetS with the International Diabetes Federation definition (area under the curve 0.887, 95% confidence interval 0.852-0.922).
CONCLUSIONS
AP, VAI and TyG were reliable surrogate markers for identifying MetS in middle-aged and elderly Chinese. LAP could be a better parameter than VAI and TyG for predicting MetS in the present study.
Topics: Aged; Asian People; Biomarkers; Blood Glucose; China; Female; Humans; Intra-Abdominal Fat; Lipid Accumulation Product; Male; Metabolic Syndrome; Middle Aged; Sensitivity and Specificity; Triglycerides
PubMed: 28664593
DOI: 10.1111/jdi.12708 -
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 -
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 -
Nature Communications Jun 2023The secreted products of cells drive many functions in vivo; however, methods to link this functional information to surface markers and transcriptomes have been...
The secreted products of cells drive many functions in vivo; however, methods to link this functional information to surface markers and transcriptomes have been lacking. By accumulating secretions close to secreting cells held within cavity-containing hydrogel nanovials, we demonstrate workflows to analyze the amount of IgG secreted from single human B cells and link this information to surface markers and transcriptomes from the same cells. Measurements using flow cytometry and imaging flow cytometry corroborate the association between IgG secretion and CD38/CD138. By using oligonucleotide-labeled antibodies we find that upregulation of pathways for protein localization to the endoplasmic reticulum and mitochondrial oxidative phosphorylation are most associated with high IgG secretion, and uncover surrogate plasma cell surface markers (e.g., CD59) defined by the ability to secrete IgG. Altogether, this method links quantity of secretion with single-cell sequencing (SEC-seq) and enables researchers to fully explore the links between genome and function, laying the foundation for discoveries in immunology, stem cell biology, and beyond.
Topics: Humans; Plasma Cells; B-Lymphocytes; Cell Membrane; Biomarkers; Immunoglobulin G
PubMed: 37322036
DOI: 10.1038/s41467-023-39367-8 -
Annals of Neurology Mar 2023While dietary intake is linked to stroke risk, surrogate markers that could inform personalized dietary interventions are lacking. We identified metabolites associated... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
While dietary intake is linked to stroke risk, surrogate markers that could inform personalized dietary interventions are lacking. We identified metabolites associated with diet patterns and incident stroke in a nested cohort from the REasons for Geographic and Racial Differences in Stroke (REGARDS) study.
METHODS
Levels of 162 metabolites were measured in baseline plasma from stroke cases (n = 1,198) and random controls (n = 904). We examined associations between metabolites and a plant-based diet pattern previously linked to reduced stroke risk in REGARDS. Secondary analyses included 3 additional stroke-associated diet patterns: a Mediterranean, Dietary Approaches to Stop Hypertension (DASH), and Southern diet. Metabolites were tested using Cox proportional hazards models with incident stroke as the outcome. Replication was performed in the Jackson Heart Study (JHS). Inverse odds ratio-weighted mediation was used to determine whether metabolites mediated the association between a plant-based diet and stroke risk.
RESULTS
Metabolites associated with a plant-based diet included the gut metabolite indole-3-propionic acid (β = 0.23, 95% confidence interval [CI] [0.14, 0.33], p = 1.14 × 10 ), guanosine (β = -0.13, 95% CI [-0.19, -0.07], p = 6.48 × 10 ), gluconic acid (β = -0.11, 95% CI [-0.18, -0.04], p = 2.06 × 10 ), and C7 carnitine (β = -0.16, 95% CI [-0.24, -0.09], p = 4.14 × 10 ). All of these metabolites were associated with both additional diet patterns and altered stroke risk. Mediation analyses identified guanosine (32.6% mediation, p = 1.51 × 10 ), gluconic acid (35.7%, p = 2.28 × 10 ), and C7 carnitine (26.2%, p = 1.88 × 10 ) as mediators linking a plant-based diet to reduced stroke risk.
INTERPRETATION
A subset of diet-related metabolites are associated with risk of stroke. These metabolites could serve as surrogate markers that inform dietary interventions. ANN NEUROL 2023;93:500-510.
Topics: Humans; Biomarkers; Carnitine; Diet; Risk Factors; Stroke
PubMed: 36373825
DOI: 10.1002/ana.26552