Categories Of Biomarkers Research Articles

Redox-related biomarkers in physical exercise

Research in redox biology of exercise has made considerable advances in the last 70 years. Since the seminal study of George Pake's group calculating the content of free radicals in skeletal muscle in resting conditions in 1954, many discoveries have been made in the field. The first section of this review is devoted to highlight the main research findings and fundamental changes in the exercise redox biology discipline. It includes: i) the first steps in free radical research, ii) the relation between exercise and oxidative damage, iii) the redox regulation of muscle fatigue, iv) the sources of free radicals during muscle contractions, and v) the role of reactive oxygen species as regulators of gene transcription and adaptations in skeletal muscle.In the second section of the manuscript, we review the available biomarkers for assessing health, performance, recovery during exercise training and overtraining in the sport population. Among the set of biomarkers that could be determined in exercise studies we deepen on the four categories of redox biomarkers: i) oxidants, ii) antioxidants, iii) oxidation products (markers of oxidative damage), and iv) measurements of the redox balance (markers of oxidative stress). The main drawbacks, strengths, weaknesses, and methodological considerations of every biomarker are also discussed.

Redox biomarkers in dietary interventions and nutritional observation studies - From new insights to old problems

PurposeThe purpose of this review is to give an overview on recently published articles investigating the associations of diet and dietary interventions with biomarkers of oxidative stress with special emphasis on different categories of redox biomarkers. FindingsIntervention and observational studies both in healthy participants and patients that investigated associations of dietary habits, foodstuffs or isolated nutrients with biomarkers of oxidative stress were included in this review. Recently published observation studies confirm the inverse association between fruit and vegetable intake and oxidative stress markers. Studies investigating the effect of vitamin D and vitamin E, magnesium, zinc, chromium, selenium, probiotic supplementation and several phytochemicals reported consistent changes in redox biomarkers. Of 88 articles included in this review, only seven studies measured biomarkers from the three categories: oxidative damage, endogenous antioxidants, and exogenous antioxidants. Many studies rely on controversial assays for total antioxidant capacity, thus there is potential in many studies to improve biomarker repertoire to cover all three categories of biomarkers and to turn away from such assays.

Targeting for Success: Demonstrating Proof-of-Concept with Mechanistic Early Phase Clinical Pharmacology Studies for Disease-Modification in Neurodegenerative Disorders.

The clinical failure rate for disease-modifying treatments (DMTs) that slow or stop disease progression has been nearly 100% for the major neurodegenerative disorders (NDDs), with many compounds failing in expensive and time-consuming phase 2 and 3 trials for lack of efficacy. Here, we critically review the use of pharmacological and mechanistic biomarkers in early phase clinical trials of DMTs in NDDs, and propose a roadmap for providing early proof-of-concept to increase R&D productivity in this field of high unmet medical need. A literature search was performed on published early phase clinical trials aimed at the evaluation of NDD DMT compounds using MESH terms in PubMed. Publications were selected that reported an early phase clinical trial with NDD DMT compounds between 2010 and November 2020. Attention was given to the reported use of pharmacodynamic (mechanistic and physiological response) biomarkers. A total of 121 early phase clinical trials were identified, of which 89 trials (74%) incorporated one or multiple pharmacodynamic biomarkers. However, only 65 trials (54%) used mechanistic (target occupancy or activation) biomarkers to demonstrate target engagement in humans. The most important categories of early phase mechanistic and response biomarkers are discussed and a roadmap for incorporation of a robust biomarker strategy for early phase NDD DMT clinical trials is proposed. As our understanding of NDDs is improving, there is a rise in potentially disease-modifying treatments being brought to the clinic. Further increasing the rational use of mechanistic biomarkers in early phase trials for these (targeted) therapies can increase R&D productivity with a quick win/fast fail approach in an area that has seen a nearly 100% failure rate to date.

Biomarkers of Response to Biologic Therapy in Juvenile Idiopathic Arthritis.

Background: Juvenile idiopathic arthritis (JIA) is the most common chronic inflammatory arthritis of childhood, characterized by various clinical phenotypes associated with variable prognosis. Significant progress has been achieved with the use of biologic treatments, which specifically block pro-inflammatory molecules involved in the disease pathogenesis. The most commonly used biologics in JIA are monoclonal antibodies and recombinant proteins targeting interleukins 1 (IL-1) and 6 (IL-6), and tumor necrosis factor α (TNF-α). Several biomarkers have been investigated in JIA. Aims: To assess the level of evidence available regarding the role of biomarkers in JIA related to guiding clinical and therapeutic decisions, providing disease prognostic information, facilitating disease activity monitoring and assessing biologic treatment response in JIA, as well as propose new strategies for biologic therapy-related biomarker use in JIA. Methods: We searched PubMed for relevant literature using predefined key words corresponding to several categories of biomarkers to assess their role in predicting and assessing biologic treatment response and clinical remission in JIA. Results: We reviewed serological, cellular, genetic, transcriptomic and imaging biomarkers, to identify candidates that are both well-established and widely used, as well as newly investigated in JIA on biologic therapy. We evaluated their role in management of JIA as well as identified the unmet needs for new biomarker discovery and better clinical applications. Conclusion: Although there are no ideal biomarkers in JIA, we identified serological biomarkers with potential clinical utility. We propose strategies of combining biomarkers of response to biologics in JIA, as well as routine implementation of clinically acceptable imaging biomarkers for improved disease assessment performance.

Redox-related biomarkers in human cardiovascular disease - classical footprints and beyond

Global epidemiological studies show that chronic non-communicable diseases such as atherosclerosis and metabolic disorders represent the leading cause of premature mortality and morbidity. Cardiovascular disease such as ischemic heart disease is a major contributor to the global burden of disease and the socioeconomic health costs. Clinical and epidemiological data show an association of typical oxidative stress markers such as lipid peroxidation products, 3-nitrotyrosine or oxidized DNA/RNA bases with all major cardiovascular diseases. This supports the concept that the formation of reactive oxygen and nitrogen species by various sources (NADPH oxidases, xanthine oxidase and mitochondrial respiratory chain) represents a hallmark of the leading cardiovascular comorbidities such as hyperlipidemia, hypertension and diabetes. These reactive oxygen and nitrogen species can lead to oxidative damage but also adverse redox signaling at the level of kinases, calcium handling, inflammation, epigenetic control, circadian clock and proteasomal system. The in vivo footprints of these adverse processes (redox biomarkers) are discussed in the present review with focus on their clinical relevance, whereas the details of their mechanisms of formation and technical aspects of their detection are only briefly mentioned. The major categories of redox biomarkers are summarized and explained on the basis of suitable examples. Also the potential prognostic value of redox biomarkers is critically discussed to understand what kind of information they can provide but also what they cannot achieve.

Biofluid Biomarkers in Traumatic Brain Injury: A Systematic Scoping Review.

Emerging evidence suggests that biofluid-based biomarkers have diagnostic and prognostic potential in traumatic brain injuries (TBI). However, owing to the lack of a conceptual framework or comprehensive review, it is difficult to visualize the breadth of materials that might be available. We conducted a systematic scoping review to map and categorize the evidence regarding biofluid-based biochemical markers of TBI. A comprehensive search was undertaken in January 2019. Of 25,354 records identified through the literature search, 1036 original human studies were included. Five hundred forty biofluid biomarkers were extracted from included studies and classified into 19 distinct categories. Three categories of biomarkers including cytokines, coagulation tests, and nerve tissue proteins were investigated more than others and assessed in almost half of the studies (560, 515, and 502 from 1036 studies, respectively). S100 beta as the most common biomarker for TBI was tested in 21.2% of studies (220 articles). Cortisol was the only biomarker measured in blood, cerebrospinal fluid, urine, and saliva. The most common sampling time was at admission and within 24h of injury. The included studies focused mainly on biomarkers from blood and central nervous system sources, the adult population, and severe and blunt injuries. The most common outcome measures used in studies were changes in biomarker concentration level, Glasgow coma scale, Glasgow outcome scale, brain computed tomography scan, and mortality rate. Biofluid biomarkers could be clinically helpful in the diagnosis and prognosis of TBI. However, there was no single definitive biomarker with accurate characteristics. The present categorization would be a road map to investigate the biomarkers of the brain injury cascade separately and detect the most representative biomarker of each category. Also, this comprehensive categorization could provide a guiding framework to design combined panels of multiple biomarkers.

Diagnostic and therapeutic potential of exosomal miRNAs in Alzheimer's disease.

Diagnostic and therapeutic potential of exosomal miRNAs in Alzheimer's disease.

Correlations between colorectal cancer biomarkers

This short review describes the main biomarkers used in research and clinical practice for colon cancer. There are several categories of biomarkers, depending on the substrate they represent or the method of harvesting. We will discuss about genetic biomarkers like microsatellite instability, KRAS, BRAF etc. Blood-based biomarkers available to monitor patients with colorectal cancer are represented by CEA and carbohydrate antigen 19-9 (CA19-9). CEA, a high molecular weight glycoprotein, is found in embryonic tissue and colorectal malignancies. We also present the stool markers. These markers are useful for screening patients at risk to develop colon cancer. The markers are also used to monitor the progression of the disease and the results of systemic therapy.

How Your Blood Knows Your Brain Is Sick

Alzheimer’s disease (AD) is a complex disease that attacks the brain that mostly affects people 65 years and older. AD affects more and more people each year. A major problem with AD is that it is diagnosed too late. A big goal is to find ways to help doctors identify the disease early, so they can better help AD patients. Biomarkers are something that can tell you if a part of the body is feeling healthy or is being attacked by a disease. This article will describe one exciting new category of biomarkers that carry information from the brain into the blood. These biomarkers can be used to see how healthy the brain is feeling or if it is getting hurt by a disease like AD.

Myocardial Infarction in the ISCHEMIA Trial: Impact of Different Definitions on Incidence, Prognosis, and Treatment Comparisons.

In the ISCHEMIA trial (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches), an initial invasive strategy did not significantly reduce rates of cardiovascular events or all-cause mortality in comparison with a conservative strategy in patients with stable ischemic heart disease and moderate/severe myocardial ischemia. The most frequent component of composite cardiovascular end points was myocardial infarction (MI). ISCHEMIA prespecified that the primary and major secondary composite end points of the trial be analyzed using 2 MI definitions. For procedural MI, the primary MI definition used creatine kinase-MB as the preferred biomarker, whereas the secondary definition used cardiac troponin. Procedural thresholds were >5 times the upper reference level for percutaneous coronary intervention and >10 times for coronary artery bypass grafting. Procedural MI definitions included (1) a category of elevated biomarker only events with much higher biomarker thresholds, (2) new ST-segment depression of ≥1 mm for the primary and ≥0.5 mm for the secondary definition, and (3) new coronary dissections >National Heart, Lung, and Blood Institute grade 3. We compared MI type, frequency, and prognosis by treatment assignment using both MI definitions. Procedural MIs accounted for 20.1% of all MI events with the primary definition and 40.6% of all MI events with the secondary definition. Four-year MI rates in patients undergoing revascularization were more frequent with the invasive versus conservative strategy using the primary (2.7% versus 1.1%; adjusted hazard ratio [HR], 2.98 [95% CI, 1.87-4.73]) and secondary (8.2% versus 2.0%; adjusted HR, 5.04 [95% CI, 3.64-6.97]) MI definitions. Type 1 MIs were less frequent with the invasive versus conservative strategy using the primary (3.40% versus 6.89%; adjusted HR, 0.53 [95% CI, 0.41-0.69]; P<0.0001) and secondary (3.48% versus 6.89%; adjusted HR, 0.53 [95% CI, 0.41-0.69]; P<0.0001) definitions. The risk of subsequent cardiovascular death was higher after a type 1 MI than after no MI using the primary (adjusted HR, 3.38 [95% CI, 2.03-5.61]; P<0.001) or secondary MI definition (adjusted HR, 3.52 [2.11-5.88]; P<0.001). In ISCHEMIA, type 1 MI events using the primary and secondary definitions during 5-year follow-up were more frequent with an initial conservative strategy and associated with subsequent cardiovascular death. Procedural MI rates were greater in the invasive strategy and with the use of the secondary MI definition. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01471522.

MarkerDB: an online database of molecular biomarkers.

MarkerDB is a freely available electronic database that attempts to consolidate information on all known clinical and a selected set of pre-clinical molecular biomarkers into a single resource. The database includes four major types of molecular biomarkers (chemical, protein, DNA [genetic] and karyotypic) and four biomarker categories (diagnostic, predictive, prognostic and exposure). MarkerDB provides information such as: biomarker names and synonyms, associated conditions or pathologies, detailed disease descriptions, detailed biomarker descriptions, biomarker specificity, sensitivity and ROC curves, standard reference values (for protein and chemical markers), variants (for SNP or genetic markers), sequence information (for genetic and protein markers), molecular structures (for protein and chemical markers), tissue or biofluid sources (for protein and chemical markers), chromosomal location and structure (for genetic and karyotype markers), clinical approval status and relevant literature references. Users can browse the data by conditions, condition categories, biomarker types, biomarker categories or search by sequence similarity through the advanced search function. Currently, the database contains 142 protein biomarkers, 1089 chemical biomarkers, 154 karyotype biomarkers and 26 374 genetic markers. These are categorized into 25 560 diagnostic biomarkers, 102 prognostic biomarkers, 265 exposure biomarkers and 6746 predictive biomarkers or biomarker panels. Collectively, these markers can be used to detect, monitor or predict 670 specific human conditions which are grouped into 27 broad condition categories. MarkerDB is available at https://markerdb.ca.

Prediction of Alzheimer\u2019s disease biomarker status defined by the \u2018ATN framework\u2019 among cognitively healthy individuals: results from the EPAD longitudinal cohort study

BackgroundThe Amyloid/Tau/Neurodegeneration (ATN) framework has been proposed as a means of evidencing the biological state of Alzheimer’s disease (AD). Predicting ATN status in pre-dementia individuals therefore provides an important opportunity for targeted recruitment into AD interventional studies. We investigated the extent to which ATN-defined biomarker status can be predicted by known AD risk factors as well as vascular-related composite risk scores.MethodsOne thousand ten cognitively healthy older adults were allocated to one of five ATN-defined biomarker categories. Multinomial logistic regression tested risk factors including age, sex, education, APOE4, family history of dementia, cognitive function, vascular risk indices (high systolic blood pressure, body mass index (BMI), high cholesterol, physical inactivity, ever smoked, blood pressure medication, diabetes, prior cardiovascular disease, atrial fibrillation and white matter lesion (WML) volume), and three vascular-related composite scores, to predict five ATN subgroups; ROC curve models estimated their added value in predicting pathology.ResultsAge, APOE4, family history, BMI, MMSE and white matter lesions (WML) volume differed between ATN biomarker groups. Prediction of Alzheimer’s disease pathology (versus normal AD biomarkers) improved by 7% after adding family history, BMI, MMSE and WML to a ROC curve that included age, sex and APOE4. Risk composite scores did not add value.ConclusionsATN-defined Alzheimer’s disease biomarker status prediction among cognitively healthy individuals is possible through a combination of constitutional and cardiovascular risk factors but established dementia composite risk scores do not appear to add value in this context.

Classification of Molecular Biomarkers

A “biomarker” is any measurable characteristic that indicates the presence or absence of disease or the biological response to a stimulus, typically an exposure or intervention. The FDA-NIH Biomarker Working Group has produced a document called Biomarkers, EndpointS and other Tools (BEST), which defines 7 categories of biomarkers according to their clinical usage: susceptibility and risk, diagnostic, monitoring, prognostic, predictive, pharmacodynamic and treatment response, and safety. We approach the classification of biomarkers in 2 additional ways: their bodily source and their measurement type. In the context of their use in genitourinary malignancy, we also consider factors that influence their use and reliability in clinical and research applications.

Biomarker Guided Therapy For Heart Failure With Mid-Range EF

Background Heart failure (HF) with mid-range ejection fraction (HFmrEF, EF 40-49%) accounts for ∼15% of HF patients and these are a heterogeneous group with a phenotypic character that reflects aspects of both preserved and reduced EF HF. There are no proven treatments for this group but identifying subsets of patients that will respond to conventional therapies such as beta blockers (BB) would be desirable. We hypothesized that HFmrEF patients with elevated Nt-proBNP or ST2 would have more favorable response to BB therapy. Methods A prospective registry was conducted that enrolled 1760 HF patients who met Framingham HF criterion and who received care through our health system and insurance product. Participants donated blood for biomarker measurements at enrollment and their medication exposure was quantified over time using pharmacy claims data. The current study utilized all participants who had EF 40-49% and baseline biomarker measurement (n=338). The primary endpoint was all-cause mortality. Biomarker categories were dichotomized at Nt-BNP >1000ng/L and ST2 ≥35ng/mL. We quantified the HR for BB exposure overall and divided by biomarker level using Cox models adjusted for MAGGIC score and BB propensity score. Results Vital status and Nt-BNP measurements were available for all 338 patients, while 279 had ST2 measured, and 201 had both markers (Table 1). For Nt-BNP, 200 (58%) had elevated levels while 143 (42%) had low values. BB use in patients with elevated Nt-BNP levels had a hazard ratio (HR) of 0.43 (p=0.1) compared to HR 0.97 (p=0.97) in the low Nt-BNP group. For ST2, 195 patients (70%) had levels 0.99) while in patients with either ST2 or Nt-BNP elevated the BB HR was 0.06 (p=0.03). Conclusions In this observational study of HFmrEF patients, those with low ST2 and Nt-BNP have low risk of death and little benefit of BB therapy whereas among the approximately two-thirds of patients with either marker elevated a substantial BB benefit association was seen

Cerebrospinal fluid sTREM2 in Alzheimer\u2019s disease: comparisons between clinical presentation and AT classification

Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor expressed by microglia. Its cleaved fragments, soluble TREM2 (sTREM2), can be measured in the cerebrospinal fluid (CSF). Previous studies indicate higher CSF sTREM2 in symptomatic AD; however most of these studies have included biomarker positive AD cases and biomarker negative controls. The aim of the study was to explore potential differences in the CSF level of sTREM2 and factors associated with an increased sTREM2 level in patients diagnosed with mild cognitive impairment (MCI) or dementia due to AD compared with cognitively unimpaired controls as judged by clinical symptoms and biomarker category (AT). We included 299 memory clinic patients, 62 (20.7%) with AD-MCI and 237 (79.3%) with AD dementia, and 113 cognitively unimpaired controls. CSF measures of the core biomarkers were applied to determine AT status. CSF sTREM2 was analyzed by ELISA. Patients presented with comparable CSF sTREM2 levels as the cognitively unimpaired (9.6 ng/ml [SD 4.7] versus 8.8 ng/ml [SD 3.6], p = 0.27). We found that CSF sTREM2 associated with age-related neuroinflammation and tauopathy irrespectively of amyloid β, APOE ε4 status or gender. The findings were similar in both symptomatic and non-symptomatic individuals.

Novel Blood Biomarkers for an Earlier Diagnosis of Alzheimer’s Disease: A Literature Review

Alzheimer’s disease is a neurodegenerative condition associated with neurofibrillary tangles and cortical deposition of amyloid plaques. Clinical presentation of the disease involves manifestations such as memory loss, cognitive decline and dementia with some of the earliest reported deficits being episodic memory impairment and olfactory dysfunction. Current diagnostic approaches rely on autopsy characterization of gross brain pathology, or brain imaging of biomarkers late in the disease course. The aim of this literature review is to identify and compare newly emerging and novel CSF, serum and mucosal biomarkers, with the potential of making an earlier clinical diagnosis of Alzheimer’s disease. Utilizing such techniques may allow for earlier therapeutic intervention, reduction of disability and enhancement of quality of life. Literature review and analysis was performed by screening the PubMed database for relevant studies within the past 5 years. All studies showed statistically significant (P &lt; 0.05) differences in testing between AD patients and controls. Two categories of serum biomarkers (redox-reactive antiphospholipid antibodies and microRNAs) and an olfactory mucosal marker (microRNA-206) could discriminate between early AD patients and controls with high sensitivity and specificity. In conclusion, certain studies have shown promising results with high sensitivity and specificity, high discriminative potential for Alzheimer’s disease early in its progression, and statistically significant results in larger study samples. Utilization of such diagnostic techniques should increase the efficacy of making an earlier clinical diagnosis of Alzheimer’s disease.

Prevalence of idiopathically elevated ESR and CRP in patients undergoing primary total knee arthroplasty as a function of body mass index

BackgroundErythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are commonly used inflammatory markers utilized to aid in the diagnosis of periprosthetic infection (PJI). Patients with obesity, however, are known to have elevated baseline levels of these inflammatory markers. Therefore, this retrospective study aimed to determine the relationship between elevated ESR and CRP and body mass index (BMI) in patients undergoing total knee arthroplasty (TKA). In doing so, physicians can better determine whether BMI should be taken into account when evaluating the prognostic value of elevated preoperative ESR and CRP levels for risk of PJI in primary TKA patients. MethodsThis is a retrospective case series of 181 patients who had undergone primary TKA at a single institution. Patients undergoing primary unilateral TKA were eligible unless they had undergone previous TKA, contralateral knee symptoms, or elevated white blood cell (WBC) count. A linear regression model was utilized to demonstrate the relationship between proportions of patients with elevated biomarker values and categories of BMI. Analysis of variance and independent two-sample t-tests were utilized to assess differences in mean ESR, CRP, and WBC levels between the “healthy patients” and “patients with comorbidities” subgroups within each BMI category. ResultsEligible patients (n = 181) were stratified by BMI category. Elevated ESR was associated significantly with BMI (ESR: r2 = 0.89, P < 0.001) unlike elevated CRP (r2 = 0.82, P = 0.133) and WBC count (r2 = .01; P = .626). No statistically significant differences in ESR values and WBC count between the “healthy patients” versus “patients with comorbidities” were demonstrated within any BMI category. In patients of normal weight (BMI 20–25 kg/m2), “healthy patients” had a statistically significantly higher mean CRP level than “patients with comorbidities” (1.73 mg/L vs. 0.70 mg/L, P < 0.001). There were no other statistically significant differences in mean CRP levels by health status. ConclusionCaution is advised when utilizing ESR and CRP to diagnose periprosthetic joint infection without considering BMI given that increasing preoperative levels of ESR and CRP are correlated with higher BMI.

Serum Galectin-3 Levels Are Unlikely to Be a Useful Predictive Marker for Early-onset Preeclampsia Development.

Galectin-3 (gal-3) is lectin which is presumed to interact with extracellular matrix proteins and cell surface glycoproteins in normal and pathophysiological conditions. The expression of gal-3 at the fetal-maternal interface partially overlaps that of gal-1, suggesting that an interplay between them might be important for hypertensive disorders in pregnancy like preeclampsia. The aim of our study was to test the hypothesis whether galectin-3 could be used as a predictive marker for early-onset preeclampsia development. 32 patients with early-onset preeclampsia were examined, mean age 28.8 ± 5.5; and 22 age matched normal pregnancies mean age 28.5 ± 6.0. The enzyme-linked immunosorbent assay (ELISA) was used for measuring serum galectin-3 levels. There were no significant differences between serum levels of galectin-3 in sera of preeclampsia patients compared to normal pregnant women - 14.1 ± 4.77 vs. 15.7 ± 5.95 ng/ml (p&gt;0.05). Serum galectin-3 levels correlated with maternal age (r=0.33; p=0.03) and BMI (body mass index) (r=0.52; p=0.01). Our data suggest that determination of serum galectin-3 levels may not be a useful method for prediction of early-onset preeclampsia. Studies should be aimed to other categories of biomarkers.

Cognitive reserve and rate of change in Alzheimer's and cerebrovascular disease biomarkers among cognitively normal individuals

We examined whether cognitive reserve (CR) impacts level of, or rate of change in, biomarkers of Alzheimer's disease (AD) and small-vessel cerebrovascular disease in >250 individuals who were cognitively normal and middle-aged and older at the baseline. The four primary biomarker categories commonly examined in studies of AD were measured longitudinally: cerebrospinal fluid measures of amyloid (A) and tau (T); cerebrospinal fluid and neuroimaging measures of neuronal injury (N); and neuroimaging measures of white matter hyperintensities (WMHs) to assess cerebrovascular pathology (V). CR was indexed by a composite score including years of education, reading, and vocabulary test performance. Higher CR was associated with lower levels of WMHs, particularly among those who subsequently progressed from normal cognition to MCI. CR was not associated with WMH trajectories. In addition, CR was not associated with either levels of, or rate of change in, A/T/N biomarkers. This may suggest that higher CR is associated with lifestyle factors that reduce levels of cerebrovascular disease, allowing individuals with higher CR to better tolerate other types of pathology.

Prediction and associations of preterm birth and its subtypes with eicosanoid enzymatic pathways and inflammatory markers

Endogenous signaling molecules derived from lipids, peptides, and DNA, are important regulators of physiological processes during pregnancy. The effect of their collective impact on preterm birth (delivery < 37 weeks gestation) is understudied. We aimed to characterize the associations and predictive capacity of an extensive panel of eicosanoids, immune biomarkers, oxidative stress markers, and growth factors towards preterm birth and its subtypes. We conducted a cross-sectional study of pregnant women (recruited < 15 weeks gestation) in the LIFECODES birth cohort, which included 58 cases of preterm birth and 115 controls that delivered term. Among the cases there were 31 cases who had a spontaneous preterm birth (cases who had spontaneous preterm labor and/or preterm premature rupture of membranes) and 25 that had preterm birth associated with aberrant placentation (cases who had preeclampsia and/or intrauterine growth restriction) and 2 cases that could not be sufficiently categorized as either. We analyzed single biomarker associations with each preterm birth outcome using multiple logistic regression. Adaptive elastic-net was implemented to perform a penalized multiple logistic regression on all biomarkers simultaneously to identify the most predictive biomarkers. We then organized biomarkers into biological groups and by enzymatic pathways and applied adaptive elastic-net and random forest to evaluate the accuracy of each group for predicting preterm birth cases. The majority of associations we observed were for spontaneous preterm birth, and adaptive elastic-net identified 5-oxoeicosatetraenoic acid, resolvin D1, 5,6-epoxy-eicsatrienoic acid, and 15-deoxy-12,14-prostaglandin J2 as most predictive. Overall, lipid biomarkers performed the best at separating cases from controls compared to other biomarker categories (adaptive elastic-net AUC = 0.78 [0.62, 0.94], random forest AUC = 0.84 [0.72, 0.96]). Among the enzymatic pathways that differentiate eicosanoid metabolites, we observed the highest prediction of overall preterm birth by lipoxygenase metabolites using random forest (AUC = 0.83 [0.69, 0.96]), followed by cytochrome p450 metabolites using adaptive elastic-net (AUC = 0.74 [0.52, 0.96]). In this study we translate biological hypothesis into the language of modern machine learning. Many lipid biomarkers were highly associated with overall and spontaneous preterm birth. Among eicosanoids, lipoxygenase and cytochrome p450 products performed best in identifying overall and spontaneous preterm birth. The combination of lipid biomarkers may have good utility in clinical settings to predict preterm birth.