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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 -
PloS One 2017HIV infection is associated with an increased risk of cardiovascular disease (CVD). Chronic low-grade immune activation is likely one of the driving mechanisms. This... (Review)
Review
BACKGROUND
HIV infection is associated with an increased risk of cardiovascular disease (CVD). Chronic low-grade immune activation is likely one of the driving mechanisms. This systematic review provides an overview of the evidence addressing the relation between immune markers and surrogate markers of CVD (except CIMT) in HIV infection.
METHODS
A systematic search was performed in PubMed, Embase and Cochrane Library identifying all articles from 1996 to April 2015. It addressed the relation between immune markers and surrogate markers of CVD (except Carotid Intima-media Thickness) in HIV-positive adults. Two authors, using predefined criteria, independently conducted the selection of articles, critical appraisal and extraction of the data. Analysis focused on immune markers that were assessed most frequently. The review was conducted according to the PRISMA guideline and performed as part of an overarching review registered with PROSPERO (CRD42014010516).
FINDINGS
Twenty-nine articles were selected, describing 34 immune markers and nine different CVD surrogate outcomes: coronary calcium score (13 times) and flow-mediated dilation (10 times) were used most frequently. Twenty-seven studies had a cross-sectional design. CRP, IL-6 and sVCAM-1 were assessed most frequently. None of the immune markers were clearly associated with any of the surrogate CVD outcomes. No effect estimate could be calculated due to marked heterogeneity in study populations, immune markers, outcomes and statistical approaches.
INTERPRETATION
This review could not identify a clear association between any of the immune markers and surrogate CVD outcomes. This may reflect a true lack of association, or may be explained by heterogeneity across studies and lack of follow-up data. Future research should focus on longitudinal studies measuring a select set of immune markers and surrogate CVD outcomes awaiting the primary outcome of clinical cardiovascular events.
Topics: Biomarkers; Cardiovascular Diseases; HIV Infections; HIV-1; Humans
PubMed: 28085961
DOI: 10.1371/journal.pone.0169986 -
Scandinavian Journal of Public Health Nov 2020Disparity in cardiovascular disease (CVD) mortality and risk factor levels between urban and rural regions has been confirmed worldwide. The aim of this study was to...
Disparity in cardiovascular disease (CVD) mortality and risk factor levels between urban and rural regions has been confirmed worldwide. The aim of this study was to examine how living in different community types (urban-rural) in childhood and adulthood are related to cardiovascular risk factors and surrogate markers of CVD such as carotid intima-media thickness (IMT) and left ventricular mass (LVM). The study population comprised 2903 participants (54.1% female, mean age 10.5 years in 1980) of the Cardiovascular Risk in Young Finns Study who had been clinically examined in 1980 (age 3-18 years) and had participated in at least one adult follow-up (2001-2011). In adulthood, urban residents had lower systolic blood pressure (-1 mmHg), LDL-cholesterol (-0.05 mmol/l), lower body mass index (-1.0 kg/m) and glycosylated haemoglobin levels (-0.05 mmol/mol), and lower prevalence of metabolic syndrome (19.9 v. 23.7%) than their rural counterparts. In addition, participants continuously living in urban areas had significantly lower IMT (-0.01 mm), LVM (1.59 g/m) and pulse wave velocity (-0.22 m/s) and higher carotid artery compliance (0.07%/10 mmHg) compared to persistently rural residents. The differences in surrogate markers of CVD were only partially attenuated when adjusted for cardiovascular risk factors.
Topics: Adult; Biomarkers; Cardiovascular Diseases; Carotid Intima-Media Thickness; Child; Female; Finland; Follow-Up Studies; Health Status Disparities; Heart Ventricles; Humans; Male; Middle Aged; Organ Size; Risk Factors; Rural Population; Urban Population
PubMed: 31464561
DOI: 10.1177/1403494819869816 -
Internal Medicine (Tokyo, Japan) 2014Magnetic resonance imaging has been shown to be a powerful tool for diagnosing multiple sclerosis (MS) and evaluating surrogate markers of the disease activity. However,... (Review)
Review
Magnetic resonance imaging has been shown to be a powerful tool for diagnosing multiple sclerosis (MS) and evaluating surrogate markers of the disease activity. However, biomarkers may provide more accurate information regarding ongoing immune responses leading to demyelination and treatment effects in MS patients. Although serum biomarkers are easily accessible, they do not provide clear-cut results, whereas cerebrospinal fluid (CSF) biomarkers provide unequivocal information, although samples cannot be repeatedly obtained. For diagnosis, the presence of oligoclonal IgG bands remains important. In addition, measuring the levels of adhesion molecules, matrix metalloproteinase-9 and complement regulator factor H in the serum and evaluating the proportion of Th1/Th2 cells in the blood may be clinically feasible for monitoring the disease activity. In CSF samples, increased IL-8, IL-12, IL-17, CCL3, CCL5 and CXCL10 levels indicate active disease, and the flow cytometry findings of CSF cells can be used to detect increases in Th1 and CD4(+)CD25(+) cells during relapse. Biomarkers closely linked to the disease activity may be informative of the pathogenesis of MS, while those associated with tissue damage or repair may be targets of new treatment strategies. Establishing the latter will be a primary point of research in the near future.
Topics: Biomarkers; Diagnosis, Differential; Humans; Magnetic Resonance Imaging; Multiple Sclerosis
PubMed: 24583421
DOI: 10.2169/internalmedicine.53.1246 -
Comprehensive Physiology Mar 2020The scientific community has searched for years for ways of examining neuronal tissue to track neural activity with reliable anatomical markers for stimulated neuronal... (Review)
Review
The scientific community has searched for years for ways of examining neuronal tissue to track neural activity with reliable anatomical markers for stimulated neuronal activity. Existing studies that focused on hypothalamic systems offer a few options but do not always compare approaches or validate them for dependence on cell firing, leaving the reader uncertain of the benefits and limitations of each method. Thus, in this article, potential markers will be presented and, where possible, placed into perspective in terms of when and how these methods pertain to hypothalamic function. An example of each approach is included. In reviewing the approaches, one is guided through how neurons work, the consequences of their stimulation, and then the potential markers that could be applied to hypothalamic systems are discussed. Approaches will use features of neuronal glucose utilization, water/oxygen movement, changes in neuron-glial interactions, receptor translocation, cytoskeletal changes, stimulus-synthesis coupling that includes expression of the heteronuclear or mature mRNA for transmitters or the enzymes that make them, and changes in transcription factors (immediate early gene products, precursor buildup, use of promoter-driven surrogate proteins, and induced expression of added transmitters. This article includes discussion of methodological limitations and the power of combining approaches to understand neuronal function. © 2020 American Physiological Society. Compr Physiol 10:549-575, 2020.
Topics: Animals; Biomarkers; Humans; Hypothalamus; Neurons
PubMed: 32163202
DOI: 10.1002/cphy.c170021 -
Biometrics Dec 2021The utilization of surrogate markers offers the opportunity to reduce the length of required follow-up time and/or costs of a randomized trial examining the...
The utilization of surrogate markers offers the opportunity to reduce the length of required follow-up time and/or costs of a randomized trial examining the effectiveness of an intervention or treatment. There are many available methods for evaluating the utility of a single surrogate marker including both parametric and nonparametric approaches. However, as the dimension of the surrogate marker increases, a completely nonparametric procedure becomes infeasible due to the curse of dimensionality. In this paper, we define a quantity to assess the value of multiple surrogate markers in a time-to-event outcome setting and propose a robust estimation approach for censored data. We focus on surrogate markers that are measured at some landmark time, t , which occurs earlier than the end of the study. Our approach is based on a dimension reduction procedure with an option to incorporate weights to guard against potential misspecification of the working model, resulting in three different proposed estimators, two of which can be shown to be double robust. We examine the finite sample performance of the estimators under various scenarios using a simulation study. We illustrate the estimation and inference procedures using data from the Diabetes Prevention Program (DPP) to examine multiple potential surrogate markers for diabetes.
Topics: Biomarkers; Causality; Computer Simulation; Diabetes Mellitus; Humans; Models, Statistical
PubMed: 32920821
DOI: 10.1111/biom.13370 -
Lipids in Health and Disease Nov 2022Due to the contribution of coronary artery disease (CAD) to serious cardiovascular events, determining biomarkers that could robustly predict its risk would be of utmost...
Evaluating the use of novel atherogenicity indices and insulin resistance surrogate markers in predicting the risk of coronary artery disease: a case‒control investigation with comparison to traditional biomarkers.
BACKGROUND
Due to the contribution of coronary artery disease (CAD) to serious cardiovascular events, determining biomarkers that could robustly predict its risk would be of utmost importance. Thus, this research was designed to assess the value of traditional cardio-metabolic indices, and more novel atherogenicity indices and insulin resistance surrogate markers in the identification of individuals at risk of CAD.
METHODS
A case‒control survey was conducted, in which 3085 individuals were enrolled. Their clinical and biochemical data were gathered at baseline. The investigated indices included the atherogenic index of plasma (AIP), triglyceride-glucose (TyG) index, TyG-body mass index (TyG-BMI), lipoprotein combine index (LCI), cholesterol index (CHOLINDEX), Castelli's risk indices-I, II (CRI-I, CRI-II), and metabolic score for insulin resistance (METS - IR). To examine the relationship between these variables and CAD risk, multiple regression analyses adjusted for potential confounders were conducted.
RESULTS
Overall, 774 angiographically confirmed CAD patients (mean age = 54 years) were compared with 3085 controls (mean age = 51 years). Higher triglyceride, total cholesterol and fasting blood sugar levels and lower HDL-C levels were related to an elevated risk of CAD (P-for-trend < 0.001), while the direct association between increased serum LDL-C concentrations and a greater risk of CAD only became apparent when excluding those with diabetes, and statin users. Among novel indices, greater values of the majority of these markers, including AIP, CRI-I, and -II, CHOLINDEX, LCI, and TyG-index, in comparison to the lower values, significantly elevated CAD risk (P-for-trend < 0.001).
CONCLUSION
According to the current findings, novel atherogenicity indices and insulin resistance surrogate markers, in particular, AIP, CRI-I and II, CHOLINDEX, LCI, and TyG-index, may be useful in predicting CAD risk.
Topics: Humans; Middle Aged; Insulin Resistance; Coronary Artery Disease; Blood Glucose; Biomarkers; Triglycerides; Case-Control Studies; Glucose; Risk Factors
PubMed: 36435770
DOI: 10.1186/s12944-022-01732-9 -
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 -
Pediatric Nephrology (Berlin, Germany) Feb 2015At a recent meeting of international experts on clinical aspects of progressive chronic kidney disease (CKD), an extensive analysis of extant clinical trials was used to...
At a recent meeting of international experts on clinical aspects of progressive chronic kidney disease (CKD), an extensive analysis of extant clinical trials was used to develop more effective and economical surrogate markers for CKD outcomes in adults. This article describes the reasons for this undertaking, the methods and conclusions of the meeting, and the relevance of these findings to pediatric nephrology.
Topics: Adult; Biomarkers; Child; Disease Progression; Female; Glomerular Filtration Rate; Humans; Male; Renal Insufficiency, Chronic; Treatment Outcome
PubMed: 25370779
DOI: 10.1007/s00467-014-2995-0 -
Balkan Medical Journal Feb 2020Cardiovascular diseases are one of the most common causes of death in both developing and developed countries worldwide. Even though there have been improvements in...
Cardiovascular diseases are one of the most common causes of death in both developing and developed countries worldwide. Even though there have been improvements in primary prevention, the prevalence of cardiovascular diseases continues to increase in recent years. Hence, it is crucial to both investigate the molecular pathophysiology of cardiovascular diseases in-depth and find novel biomarkers regarding the early and proper prevention and diagnosis of these diseases. MicroRNAs, or miRNAs, are endogenous, conserved, single-stranded non-coding RNAs of 21-25 nucleotides in length. miRNAs have important roles in various cellular events such as embryogenesis, proliferation, vasculogenesis, apoptosis, cell growth, differentiation, and tumorigenesis. They also have potential roles in the cardiovascular system, including angiogenesis, cardiac cell contractility, control of lipid metabolism, plaque formation, the arrangement of cardiac rhythm, and cardiac cell growth. Circulating miRNAs are promising novel biomarkers for purposes of the diagnosis and prognosis of cardiovascular diseases. Cell or tissue specificity, stability in serum or plasma, resistance to degradative factors such as freeze-thaw cycles or enzymes in the blood, and fast-release kinetics, provide the potential for miRNAs to be surrogate markers for the early and accurate diagnosis of disease and for predicting middle- or long-term prognosis. Moreover, it may be a logical approach to combine miRNAs with traditional biomarkers to improve risk stratification and long-term prognosis. In addition to their efficacy in both diagnosis and prognosis, miRNA-based therapeutics may be beneficial for treating cardiovascular diseases using novel platforms and computational tools and in combination with traditional methods of analysis. microRNAs are promising, novel therapeutic agents, which can affect multiple genes using different signaling pathways. miRNAs therapeutic modulation techniques have been used in the settings of atherosclerosis, acute myocardial infarction, restenosis, vascular remodeling, arrhythmias, hypertrophy and fibrosis, angiogenesis and cardiogenesis, aortic aneurysm, pulmonary hypertension, and ischemic injury. This review presents detailed information about miRNAs regarding structure and biogenesis, stages of synthesis and functions, expression profiles in serum/plasma of living organisms, diagnostic and prognostic potential as novel biomarkers, and therapeutic applications in various diseases.
Topics: Biomarkers; Cardiovascular Diseases; Humans; MicroRNAs; Prognosis
PubMed: 32018347
DOI: 10.4274/balkanmedj.galenos.2020.2020.1.94