-
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 -
Molecular Oncology Jun 2021Nucleic acids and proteins are shed into the bloodstream by tumor cells and can be exploited as biomarkers for the detection of cancer. In addition, cancer detection... (Review)
Review
Nucleic acids and proteins are shed into the bloodstream by tumor cells and can be exploited as biomarkers for the detection of cancer. In addition, cancer detection biomarkers can also be nontumor-derived, having their origin in other organs and cell types. Hence, liquid biopsies provide a source of direct tumor cell-derived biomolecules and indirect nontumor-derived surrogate markers that circulate in body fluids or are taken up by circulating peripheral blood cells. The capacity of platelets to take up proteins and nucleic acids and alter their megakaryocyte-derived transcripts and proteins in response to external signals makes them one of the richest liquid biopsy biosources. Platelets are the second most abundant cell type in peripheral blood and are routinely isolated through well-established and fast methods in clinical diagnostics but their value as a source of cancer biomarkers is relatively recent. Platelets do not have a nucleus but have a functional spliceosome and protein translation machinery, to process RNA transcripts. Platelets emerge as important repositories of potential cancer biomarkers, including several types of RNAs (mRNA, miRNA, circRNA, lncRNA, and mitochondrial RNA) and proteins, and several preclinical studies have highlighted their potential as a liquid biopsy source for detecting various types and stages of cancer. Here, we address the usability of platelets as a liquid biopsy for the detection of cancer. We describe several studies that support the use of platelet biomarkers in cancer diagnostics and discuss what is still lacking for their implementation into the clinic.
Topics: Biomarkers, Tumor; Blood Platelets; High-Throughput Nucleotide Sequencing; Humans; Liquid Biopsy; Neoplasms; Translational Research, Biomedical
PubMed: 33219615
DOI: 10.1002/1878-0261.12859 -
Biometrics Jun 2023In studies that require long-term and/or costly follow-up of participants to evaluate a treatment, there is often interest in identifying and using a surrogate marker to...
In studies that require long-term and/or costly follow-up of participants to evaluate a treatment, there is often interest in identifying and using a surrogate marker to evaluate the treatment effect. While several statistical methods have been proposed to evaluate potential surrogate markers, available methods generally do not account for or address the potential for a surrogate to vary in utility or strength by patient characteristics. Previous work examining surrogate markers has indicated that there may be such heterogeneity, that is, that a surrogate marker may be useful (with respect to capturing the treatment effect on the primary outcome) for some subgroups, but not for others. This heterogeneity is important to understand, particularly if the surrogate is to be used in a future trial to replace the primary outcome. In this paper, we propose an approach and estimation procedures to measure the surrogate strength as a function of a baseline covariate W and thus examine potential heterogeneity in the utility of the surrogate marker with respect to W. Within a potential outcome framework, we quantify the surrogate strength/utility using the proportion of treatment effect on the primary outcome that is explained by the treatment effect on the surrogate. We propose testing procedures to test for evidence of heterogeneity, examine finite sample performance of these methods via simulation, and illustrate the methods using AIDS clinical trial data.
Topics: Humans; Biomarkers; Computer Simulation
PubMed: 34874550
DOI: 10.1111/biom.13600 -
International Journal of Molecular... Apr 2016The effective and efficient management of cancer patients relies upon early diagnosis and/or the monitoring of treatment, something that is often difficult to achieve... (Review)
Review
The effective and efficient management of cancer patients relies upon early diagnosis and/or the monitoring of treatment, something that is often difficult to achieve using standard tissue biopsy techniques. Biological fluids such as blood hold great possibilities as a source of non-invasive cancer biomarkers that can act as surrogate markers to biopsy-based sampling. The non-invasive nature of these "liquid biopsies" ultimately means that cancer detection may be earlier and that the ability to monitor disease progression and/or treatment response represents a paradigm shift in the treatment of cancer patients. Below, we review one of the most promising classes of circulating cancer biomarkers: microRNAs (miRNAs). In particular, we will consider their history, the controversy surrounding their origin and biology, and, most importantly, the hurdles that remain to be overcome if they are really to become part of future clinical practice.
Topics: Biomarkers, Tumor; High-Throughput Nucleotide Sequencing; Humans; MicroRNAs; Neoplasms; Real-Time Polymerase Chain Reaction
PubMed: 27128908
DOI: 10.3390/ijms17050627 -
Seminars in Immunopathology Sep 2019Osteoarthritis (OA) is a chronic progressive, painful disease of synovial joints, characterized by cartilage degradation, subchondral bone remodeling, osteophyte... (Review)
Review
Osteoarthritis (OA) is a chronic progressive, painful disease of synovial joints, characterized by cartilage degradation, subchondral bone remodeling, osteophyte formation, and synovitis. It is now widely appreciated that the innate immune system, and in particular Toll-like receptors (TLRs), contributes to pathological changes in OA joint tissues. Furthermore, it is now also increasingly recognized that TLR signaling plays a key role in initiating and maintaining pain. Here, we reviewed the literature of the past 5 years with a focus on how TLRs may contribute to joint damage and pain in OA. We discuss biological effects of specific damage-associated molecular patterns (DAMPs) which act as TLR ligands in vitro, including direct effects on pain-sensing neurons. We then discuss the phenotype of transgenic mice that target TLR pathways, and provide evidence for a complex balance between pro- and anti-inflammatory signaling pathways activated by OA DAMPs. Finally, we summarize clinical evidence implicating TLRs in OA pathogenesis, including polymorphisms and surrogate markers of disease activity. Our review of the literature led us to propose a model where multi-directional crosstalk between connective tissue cells (chondrocytes, fibroblasts), innate immune cells, and sensory neurons in the affected joint may promote OA pathology and pain.
Topics: Alarmins; Animals; Biomarkers; Chronic Pain; Disease Progression; Disease Susceptibility; Humans; Mice; Neuroimmunomodulation; Osteoarthritis; Signal Transduction; Toll-Like Receptors
PubMed: 31612243
DOI: 10.1007/s00281-019-00762-3 -
Journal of the American Heart... Mar 2017Surrogate endpoint trials test strategies more efficiently but are accompanied by uncertainty about the relationship between changes in surrogate markers and clinical... (Review)
Review
BACKGROUND
Surrogate endpoint trials test strategies more efficiently but are accompanied by uncertainty about the relationship between changes in surrogate markers and clinical outcomes.
METHODS AND RESULTS
We identified cardiovascular trials with primary surrogate endpoints published in the , , and from 1990 to 2011 and determined the trends in publication of surrogate endpoint trials and the success of the trials in meeting their primary endpoints. We tracked for publication of clinical outcome trials on the interventions tested in surrogate trials. We screened 3016 articles and identified 220 surrogate endpoint trials. From the total of 220 surrogate trials, 157 (71.4%) were positive for their primary endpoint. Only 59 (26.8%) surrogate trials had a subsequent clinical outcomes trial. Among these 59 trials, 24 outcomes trial results validated the positive surrogates, whereas 20 subsequent outcome trials were negative following positive results on a surrogate. We identified only 3 examples in which the surrogate trial was negative but a subsequent outcomes trial was conducted and showed benefit. Findings were consistent in a sample cohort of 383 screened articles inclusive of 37 surrogate endpoint trials from 6 other high-impact journals.
CONCLUSIONS
Although cardiovascular surrogate outcomes trials frequently show superiority of the tested intervention, they are infrequently followed by a prominent outcomes trial. When there was a high-profile clinical outcomes study, nearly half of the positive surrogate trials were not validated. Cardiovascular surrogate outcome trials may be more appropriate for excluding benefit from the patient perspective than for identifying it.
Topics: Biomarkers; Cardiovascular Diseases; Clinical Trials as Topic; Endpoint Determination; Humans
PubMed: 28325713
DOI: 10.1161/JAHA.116.005285 -
International Journal of Molecular... Mar 2023Gut microbiota encompasses the set of microorganisms that colonize the gastrointestinal tract with mutual relationships that are key for host homeostasis. Increasing... (Review)
Review
Gut microbiota encompasses the set of microorganisms that colonize the gastrointestinal tract with mutual relationships that are key for host homeostasis. Increasing evidence supports cross intercommunication between the intestinal microbiome and the eubiosis-dysbiosis binomial, indicating a networking role of gut bacteria as potential metabolic health surrogate markers. The abundance and diversity of the fecal microbial community are already recognized to be associated with several disorders, such as obesity, cardiometabolic events, gastrointestinal alterations, and mental diseases, which suggests that intestinal microbes may be a valuable tool as causal or as consequence biomarkers. In this context, the fecal microbiota could also be used as an adequate and informative proxy of the nutritional composition of the food intake and about the adherence to dietary patterns, such as the Mediterranean or Western diets, by displaying specific fecal microbiome signatures. The aim of this review was to discuss the potential use of gut microbial composition as a putative biomarker of food intake and to screen the sensitivity value of fecal microbiota in the evaluation of dietary interventions as a reliable and precise alternative to subjective questionnaires.
Topics: Feces; Gastrointestinal Tract; Gastrointestinal Microbiome; Eating; Biomarkers
PubMed: 36902349
DOI: 10.3390/ijms24054918 -
Biometrics Jun 2023Identifying effective and valid surrogate markers to make inference about a treatment effect on long-term outcomes is an important step in improving the efficiency of...
Identifying effective and valid surrogate markers to make inference about a treatment effect on long-term outcomes is an important step in improving the efficiency of clinical trials. Replacing a long-term outcome with short-term and/or cheaper surrogate markers can potentially shorten study duration and reduce trial costs. There is sizable statistical literature on methods to quantify the effectiveness of a single surrogate marker. Both parametric and nonparametric approaches have been well developed for different outcome types. However, when there are multiple markers available, methods for combining markers to construct a composite marker with improved surrogacy remain limited. In this paper, building on top of the optimal transformation framework of Wang et al. (2020), we propose a novel calibrated model fusion approach to optimally combine multiple markers to improve surrogacy. Specifically, we obtain two initial estimates of optimal composite scores of the markers based on two sets of models with one set approximating the underlying data distribution and the other directly approximating the optimal transformation function. We then estimate an optimal calibrated combination of the two estimated scores which ensures both validity of the final combined score and optimality with respect to the proportion of treatment effect explained by the final combined score. This approach is unique in that it identifies an optimal combination of the multiple surrogates without strictly relying on parametric assumptions while borrowing modeling strategies to avoid fully nonparametric estimation which is subject to the curse of dimensionality. Our identified optimal transformation can also be used to directly quantify the surrogacy of this identified combined score. Theoretical properties of the proposed estimators are derived, and the finite sample performance of the proposed method is evaluated through simulation studies. We further illustrate the proposed method using data from the Diabetes Prevention Program study.
Topics: Models, Statistical; Computer Simulation; Biomarkers
PubMed: 35426444
DOI: 10.1111/biom.13677 -
Therapeutic Drug Monitoring Apr 2019Although the monitoring of drug therapies based on the determination of drug concentrations in biological materials is certainly an important instrument for...
Although the monitoring of drug therapies based on the determination of drug concentrations in biological materials is certainly an important instrument for individualized dosing and dose adjustment with a broad variety of pharmaceuticals, its role is limited by the fact that it does not reflect pharmacodynamic (PD) and toxicodynamic interactions such as those caused by individual and environment-related factors. However, these interactions are important for both the efficacy and the safety of the drug therapy. Therefore, during recent years, there is an increased interest in personalized drug therapy as reflected by the development and clinical implementation of molecular "biomarkers" that are direct or surrogate markers of pharmacological effects [PD therapeutic drug monitoring (TDM)]. Moreover, this process is driven by new developments in instrumentation, such as mass spectrometry and array technologies, and in computational biology/pharmacology, databases, and bioinformatics. This Focus Issue of the journal focuses on current achievements in and status of PD TDM with different classes of drugs. The contributions to the present issue of Therapeutic Drug Monitoring provide a critical analysis of current practices of TDM with their limitations, introduce newer promising biomarkers in the field of PD TDM, discuss the challenges faced to date in translating preclinical tools into clinical settings, and point out recent advances in the establishment of modeling approaches that apply to pharmacokinetics (PK)/PD as well as pharmacogenetic information.
Topics: Biomarkers; Drug Monitoring; Humans; Pharmacology
PubMed: 30883504
DOI: 10.1097/FTD.0000000000000627 -
Hepatology Communications Jun 2023Mucosal-associated invariant T cells (MAITs) are markedly reduced in patients with alcohol-associated liver disease (ALD); however, the potential mechanism underlying...
BACKGROUND
Mucosal-associated invariant T cells (MAITs) are markedly reduced in patients with alcohol-associated liver disease (ALD); however, the potential mechanism underlying MAITs' loss remains elusive. Hence, we aimed to explore what induced MAITs' loss and its clinical significance.
METHODS
The characteristics of pyroptotic MAITs were evaluated in a cohort of patients with ALD, including 41 patients with alcohol-associated liver cirrhosis (ALC) and 21 patients with ALC complicated with severe alcoholic hepatitis (ALC + SAH).
RESULTS
In patients with ALD, blood MAITs were significantly decreased, hyperactivated, and displayed enhanced cell death through pyroptosis. The frequencies of pyroptotic MAITs increased with disease severity in patients with ALC and patients with ALC + SAH. These frequencies were negatively associated with the frequencies of MAITs and positively correlated with the levels of MAITs' activation, plasma levels of intestinal fatty acid-binding protein (a marker of intestinal enterocyte damage), soluble CD14, lipopolysaccharide-binding protein, and peptidoglycan recognition proteins (surrogate markers of microbial translocation). Pyroptotic MAITs were also found in the liver of patients with ALD. Interestingly, MAITs underwent further activation and pyroptosis in vitro under stimulation by Escherichia coli or direct bilirubin. Notably, blocking IL-18 signaling reduced the activation and frequencies of pyroptotic MAITs.
CONCLUSIONS
The loss of MAITs in patients with ALD is, at least in part, due to cell death from pyroptosis and is associated with the severity of ALD. Such increased pyroptosis may be affected by dysregulated inflammatory responses to intestinal microbial translocation or direct bilirubin.
Topics: Humans; Liver Diseases, Alcoholic; Hepatitis, Alcoholic; Liver Cirrhosis, Alcoholic; Biomarkers; Bilirubin
PubMed: 37204414
DOI: 10.1097/HC9.0000000000000159