Individual Inflammatory Biomarkers Research Articles

New perspectives in the differential diagnosis of jaw lesions: Machine learning and inflammatory biomarkers

This study aimed to assess the diagnostic performance of a machine learning approach that utilized radiomic features extracted from Cone Beam Computer Tomography (CBCT) images and inflammatory biomarkers for distinguishing between Dentigerous Cysts (DCs), Odontogenic Keratocysts (OKCs), and Unicystic Ameloblastomas (UAs). This retrospective study involves 103 patients who underwent jaw lesion surgery in the Maxillofacial Surgery Unit of Federico II University Of Naples between January 2018 and January 2023. Nonparametric Wilcoxon-Mann-Whitney and Kruskal Wallis tests were used for continuous variables. Linear and non-logistic regression models (LRM and NLRM) were employed, along with machine learning techniques such as decision tree (DT), k-nearest neighbor (KNN), and support vector machine (SVM), to predict the outcomes. When individual inflammatory biomarkers were considered alone, their ability to differentiate between OKCs, UAs, and DCs was below 50 % accuracy. However, a linear regression model combining four inflammatory biomarkers achieved an accuracy of 95 % and an AUC of 0.96. The accuracy of single radiomics predictors was lower than that of inflammatory biomarkers, with an AUC of 0.83. The Fine Tree model, utilizing NLR, SII, and one radiomic feature, achieved an accuracy of 94.3 % (AUC = 0.95) on the training and testing sets, and a validation set accuracy of 100 %. The Fine Tree model demonstrated the capability to discriminate between OKCs, UAs, and DCs. However, the LRM utilizing four inflammatory biomarkers proved to be the most effective algorithm for distinguishing between OKCs, UAs, and DCs.

Clinical value of the low-grade inflammation score in aneurysmal subarachnoid hemorrhage

Background and purposeMultiple inflammatory biomarkers have been shown to predict symptomatic cerebral vasospasm (SCVS) and poor functional outcome in patients with aneurysmal subarachnoid hemorrhage. However, the impact of the low-grade inflammation (LGI) score, which can reflect the synergistic effects of five individual inflammatory biomarkers on SCVS and poor functional outcome on aneurysmal subarachnoid hemorrhage (aSAH), has not yet been well established. The aim of this study was to evaluate the impact of the LGI score on SCVS and poor functional outcome in aSAH patients.MethodsThe LGI score was calculated as the sum of 10 quantiles of each individual inflammatory biomarker. The association of the LGI score with the risk of SCVS and poor functional outcome was analyzed with multivariate logistical regression.ResultsA total of 270 eligible aSAH patients were included in this study: 74 (27.4%) had SCVS, and 79 (29.3%) had poor functional outcomes. After adjusting for confounders, a higher LGI score was revealed to independently predict SCVS (OR, 1.083; 95% CI, 1.011–1.161; P = 0.024) and poor functional outcome (OR, 1.132; 95% CI, 1.023–1.252; P = 0.016), and the second and third tertile group had higher risk of SCVS than lowest tertile group (OR, 2.826; 95% CI, 1.090–7.327; P = 0.033) (OR, 3.243; 95% CI, 1.258–8.358; P = 0.015). The receiver operating characteristic (ROC) curve uncovered the ability of the LGI score to distinguish patients with and without SCVS (area under the curve [AUC] = 0.746; 95% CI, 0.690–0.797; P < 0.001) and poor functional outcomes (area under the curve [AUC] = 0.799; 95% CI, 0.746–0.845; P < 0.001), the predictive value of LGI on SCVS and poor functional outcome is superior than PLT, NLR and WBC, but there was no statistical difference between LGI and CRP for predicting SCVS (P = 0.567) and poor functional outcome (P = 0.171).ConclusionsA higher LGI which represents severe low grade inflammation status is associated with SCVS and poor functional outcome at 3 months after aSAH.

Inflammatory biomarkers and cerebral small vessel disease: a community-based cohort study

Background and purposeAlthough inflammation has been proposed to be a candidate risk factor for cerebral small vessel disease (CSVD), previous findings remain largely inconclusive and vary according to disease status...

Using principal component analysis to examine associations of early pregnancy inflammatory biomarker profiles and adverse birth outcomes

Inflammation as a risk factor for preterm birth is well-established. The primary objective of this analysis was to examine whether individual cytokines versus a composite indicator of mid-pregnancy inflammation are significantly associated with risk for adverse birth outcomes. A multi-site prospective study was conducted in a socio-demographically diverse cohort of 610 pregnant participants. At a study visit between 12 and 20 6/7 weeks' gestation, low-grade inflammation was measured via log-transformed serum concentrations of the biomarkers IFN-γ, IL-10, IL-13, IL-6, IL-8, TNF-α, and CRP. Principal component analysis (PCA) was used to identify underlying dimensions of inflammatory activity from the seven biomarkers measured. Gestational age and birth weight at delivery were obtained from medical chart review. The associations between inflammatory profiles and birth outcomes were assessed via linear and logistic regression models. Results were compared with those from individual inflammatory biomarkers, and model fit was assessed using Akaike's Information Criterion (AIC). Principal component analysis analysis yielded a two-factor solution, with the first factor (IF1) composed of IL-8, IL-10, IL-13, IFN-ɣ, and TNF-α, and the second factor (IF2) containing IL-6 and CRP. When adjusted for race, education, BMI, smoking status, gestational age at time of blood draw, and study site, a one standard deviation (SD) increase in IF1 remained significantly associated with a decrease in standardized gestational age (β=-.13, 95% CI: -.21, -.05) and an increase in odds of preterm delivery (OR=1.46, 95% CI: 1.13, 1.88) (Table 3). A one SD increase in IF2 was similarly associated with a decrease in standardized gestational age at delivery (β=-.13, 95% CI: -.23, -.04) and an increase in odds of preterm delivery (OR: 1.46, 95% CI: 1.04, 2.05). Neither IF1 nor IF2 was associated with measures of fetal growth. AIC identified that IL-6 was a slightly better fit for length of gestation compared to either composite measure, though all performed similarly. Independent of known sociodemographic risk factors, an elevated mid-pregnancy inflammatory profile was associated with a nearly 50% increase in odds of preterm delivery. The composite performed similarly to IL-6. These results suggest that maternal low-grade inflammation is a risk factor for preterm delivery, and that mid-pregnancy inflammatory biomarkers may be useful in predicting risk for preterm delivery.

Is replacing sedentary time with bouts of physical activity associated with inflammatory biomarkers in children?

This study aimed to investigate the theoretical impact of reallocating a specific amount of sedentary time with an equal amount of (a) total and (b) ≥1-minute bout-accumulated time spent in different activity intensities, on inflammatory biomarkers in 8- to 9-year-old children. Accelerometry and inflammatory biomarker baseline data from the Transform-Us! Study (complete cases n=149) were utilized. Isotemporal linear models with the Gaussian distribution and identity link functions were used to assess associations between the activity replacements and seven individual inflammatory biomarkers, including C-reactive protein (CRP), and Interleukin (IL)-2, IL-6, IL-8, and IL-10, as well as combined inflammatory and pro-inflammatory composite scores. Eighty-five percent of children met physical activity recommendations. Replacing 10minutes of sedentary time per day with VPA, regardless of how this was accumulated, was beneficially associated with CRP and both combined composite scores. In contrast, replacing 10min/day of sedentary time with≥1-minute MPA bouts was detrimentally associated with CRP and the inflammatory composite score. Substitutions with other activity intensities were not significantly associated with any individual inflammatory biomarkers, or combined inflammatory and pro-inflammatory composite scores. In healthy and active school-aged children, evidence of the theoretical impact of replacing sedentary time with physical activity, regardless of intensity or accumulation, on markers of systemic inflammation was limited. Longitudinal research is needed to investigate the long-term impacts of reallocating sedentary time with physical activity, and particularly VPA, for inflammatory biomarkers in children, including those with increased risk of inflammation.

Development and Validation of an Inflammatory-Frailty Index for Kidney Transplantation.

Physical frailty phenotype is characterized by decreased physiologic reserve to stressors and associated with poor outcomes, such as delirium and mortality, that may result from post-kidney transplant (KT) inflammation. Despite a hypothesized underlying pro-inflammatory state, conventional measures of frailty typically do not incorporate inflammatory biomarkers directly. Among KT candidates and recipients, we evaluated the inclusion of inflammatory biomarkers with traditional physical frailty phenotype components. Among 1154 KT candidates and recipients with measures of physical frailty phenotype and inflammation (interleukin 6 [IL6], tumor necrosis factor alpha [TNFα], C-reactive protein [CRP]) at 2 transplant centers (2009-2017), we evaluated construct validity of inflammatory-frailty using latent class analysis. Inflammatory-frailty measures combined 5 physical frailty phenotype components plus the addition of an individual inflammatory biomarkers, separately (highest tertiles) as a sixth component. We then used Kaplan-Meier methods and adjusted Cox proportional hazards to assess post-KT mortality risk by inflammatory-frailty (n = 378); Harrell's C-statistics assessed risk prediction (discrimination). Based on fit criteria, a 2-class solution (frail vs nonfrail) for inflammatory-frailty was the best-fitting model. Five-year survival (frail vs nonfrail) was: 81% versus 93% (IL6-frailty), 87% versus 89% (CRP-frailty), and 83% versus 91% (TNFα-frailty). Mortality was 2.07-fold higher for IL6-frail recipients (95% CI: 1.03-4.19, p = .04); there were no associations between the mortality and the other inflammatory-frailty indices (TNFα-frail: 1.88, 95% CI: 0.95-3.74, p = .07; CRP-frail: 1.02, 95% CI: 0.52-2.03, p = .95). However, none of the frailty-inflammatory indices (all C-statistics = 0.71) improved post-KT mortality risk prediction over the physical frailty phenotype (C-statistics = 0.70). Measurement of IL6-frailty at transplantation can inform which patients should be targeted for pre-KT interventions. However, the traditional physical frailty phenotype is sufficient for post-KT mortality risk prediction.

Longitudinal Associations between Obesity, Inflammation, and the Incidence of Type 2 Diabetes Mellitus among US Black and White Adults in the CARDIA Study.

Aim Assess prospective relationships between obesity and inflammation on the incidence of type 2 diabetes mellitus (T2DM). Methods A cohort of nondiabetic respondents from the Coronary Artery Risk Development in Young Adults (CARDIA) study was followed from 2005-2006 (wave 7) to 2010-2011 (wave 8). Diabetes status was determined in wave 8 based on self-report, blood glucose level, and anti-hyperglycemic medication use in conjunction with a homeostatic model assessment-based classification for distinguishing diabetes subtype. We performed a series of multivariable logistic regression analyses to assess the relative influence of obesity (waist circumference) and individual inflammatory biomarkers (i.e., C-reactive protein, fibrinogen, and sex-specific serum uric acid and gamma-glutamyltransferase) on the odds of developing incident T2DM between waves 7 and 8. Results Among 2784 nondiabetic CARDIA respondents, 146 (5.2%) new cases of T2DM were identified between waves. Having a high waist circumference (AOR = 6.15; 95%CI = 4.14, 9.14) and being Black (vs. White) (AOR = 1.60; 95%CI = 1.05, 2.44) were associated with T2DM. Adjusting for inflammation biomarkers attenuated the effects of waist circumference and race with T2DM. Clinically elevated CRP (AOR = 1.83; 95%CI = 1.18, 2.82) and uric acid (AOR = 2.57; 95%CI = 1.70, 3.89) predicted T2DM among all respondents. However, stratification by race showed greater attenuation of the effects of waist circumference on T2DM in Whites than in Blacks when inflammation biomarkers were accounted for in the model. Conclusion Targeted control of systemic inflammation may reduce the risk of developing T2DM, especially among Blacks, and could help address Black-White disparities in diabetes care and outcomes.

Inflammatory Frailty Index and Mortality after Kidney Transplantation

Frailty is a clinical phenotype of decreased physiologic reserve to stressors and is associated with a pro-inflammatory state. Fried frailty (measured by 5 components: slowed walk speed, unintentional weight loss, decreased grip strength, low physical activity, and exhaustion) was developed and validated in community dwelling older adults and is associated with poor outcomes after kidney transplant (KT) including mortality, longer length of stay after KT, early hospital readmission, and delayed graft function. However, Fried frailty does not directly capture inflammatory biomarkers like interleukin 6 (IL6) and tumor necrosis factor alpha (TNFalpha) that are associated with increased post-KT mortality. Therefore, we sought to identify a novel frailty index that combines inflammatory biomarkers and measured physical components. Methods We identified 378 KT recipients at Johns Hopkins Hospital from 2009-2013 who consented to enrollment in a prospective cohort. Fried frailty and inflammatory markers (IL6, TNFalpha, highly sensitive C reactive protein [(HSCRP]) were collected at the time of admission for KT. We evaluated novel inflammatory-frailty indices combining Fried frailty phenotype (comprised of 5 components) plus the addition of individual inflammatory biomarkers (highest tertile of IL6, TNFalpha, HSCRP, or inflammatory index, separately) as a 6th component. Therefore, scores for each novel inflammatory frailty index were 0-6 points, and the presence of ≥3 components was considered frail. We used Kaplan-Meier methods and Cox proportional hazards model to assess mortality risk after KT by inflammatory frailty index. We adjusted Cox models for recipient age, sex, race, Charlson comorbidity index, and donor type. Results Five-year survival for patients with and without each novel inflammatory frailty index for frail vs nonfrail was: 81% vs 93% (IL6-frailty), 87% vs 89% (HSCRP-frailty), 83% vs 91% (TNFalpha-frailty), and 83% vs 91% (Inflammatory index-frailty). After adjustment, mortality was 2.04-fold higher for IL6-frail recipients compared to non-IL6-frail (95%CI:1.02-4.10, p=0.05); there were no associations between the mortality and the other inflammatory-frailty indices (HSCRP-frail:1.01,95%CI:0.51-0.98,p=0.9; TNFalpha-frail:1.94,95%CI:0.98-3.83,p=0.06; or inflammatory index-frail:1.66,95%CI:0.84-3.30,p=0.14) recipients. After adjustment, mortality was similar between nonfrail and frail KT recipients measured with Fried frailty (1.63,95%CI:0.75-3.51, p=0.2) and the highest tertile of IL-6 (1.37,95%CI:0.68-2.73, p=0.4). Conclusions IL-6 frailty is a unique frailty phenotype, combining biomarkers and physical components that improves upon the Fried frailty phenotype and is more strongly associated with post-KT mortality. Measurement of biomarkers at KT evaluation and transplantation can guide risk assessment and patient counseling. National Institutes of Health.

Higher dietary anthocyanin and flavonol intakes are associated with anti-inflammatory effects in a population of US adults

Background: Although growing evidence from trials and population-based studies has supported a protective role for flavonoids in relation to risk of certain chronic diseases, the underlying mechanisms remain unclear. Several previous studies focused on individual inflammatory biomarkers, but because of the limited specificity of any individual marker, an assessment of a combination of biomarkers may be more informative.Objective: We used an inflammation score (IS) that integrated 12 individual inflammatory biomarkers for the examination of associations with intakes of different flavonoid classes.Design: The study was a cross-sectional analysis of 2375 Framingham Heart Study Offspring Cohort participants. Intakes of total flavonoids and their classes (anthocyanins, flavonols, flavanones, flavan-3-ols, polymers, and flavones) were calculated from validated food-frequency questionnaires. Individual inflammatory biomarkers were ranked, standardized, and summed to derive an overall IS and subgroup scores of functionally related biomarkers.Results: In multivariate analyses, an inverse association between higher anthocyanin and flavonol intakes and IS was observed with a mean ± SE difference between quintile categories 5 and 1 of −1.48 ± 0.32 (P-trend ≤ 0.001) and −0.72 ± 0.33 (P-trend = 0.01), respectively. Results remained significant after additional adjustment for physical activity and vitamin C and fruit and vegetable intakes. Higher anthocyanin intake was inversely associated with all biomarker subgroups, whereas higher flavonol intake was associated only with lower cytokine and oxidative stress biomarker concentrations. In food-based analyses, higher intakes of apples and pears, red wine, and strawberries were associated with a lower IS with differences between quintiles 5 and 1 of −1.02 ± 0.43 (P = 0.006), −1.73 ± 0.39 (P < 0.001), and −0.44 ± 0.88 (P = 0.02), respectively. Although intakes of other classes were not associated with a reduction in overall IS, higher intakes of flavan-3-ols and their polymers were associated with a significant reduction in oxidative stress biomarkers.Conclusion: These findings provide evidence to suggest that an anti-inflammatory effect may be a key component underlying the reduction in risk of certain chronic diseases associated with higher intakes of anthocyanins and flavonols. The Framingham Offspring Study was registered at clinicaltrials.gov as NCT00005121 (Framingham Heart Study).

Patterns of circulating inflammatory biomarkers in older persons with varying levels of physical performance: a partial least squares-discriminant analysis approach.

Background: Chronic, low-grade inflammation and declining physical function are hallmarks of the aging process. However, previous attempts to correlate individual inflammatory biomarkers with physical performance in older people have produced mixed results. Given the complexity of the inflammatory response, the simultaneous analysis of an array of inflammatory mediators may provide more insights into the relationship between inflammation and age-related physical function decline. This study was designed to explore the association between a panel of inflammatory markers and physical performance in older adults through a multivariate statistical approach.Methods: Community-dwelling older persons were categorized into “normal walkers” (NWs; n = 27) or “slow walkers” (SWs; n = 11) groups using 0.8 m s−1 as the 4-m gait speed cutoff. A panel of 14 circulating inflammatory biomarkers was assayed by multiplex analysis. Partial least squares-discriminant analysis (PLS-DA) was used to identify patterns of inflammatory mediators associated with gait speed categories.Results: The optimal complexity of the PLS-DA model was found to be five latent variables. The proportion of correct classification was 88.9% for NW subjects (74.1% in cross-validation) and 90.9% for SW individuals (81.8% in cross-validation). Discriminant biomarkers in the model were interleukin 8, myeloperoxidase, and tumor necrosis factor alpha (all higher in the SW group), and P-selectin, interferon gamma, and granulocyte–macrophage colony-stimulating factor (all higher in the NW group).Conclusion: Distinct profiles of circulating inflammatory biomarkers characterize older subjects with different levels of physical performance. The dissection of these patterns may provide novel insights into the role played by inflammation in the disabling cascade and possible new targets for interventions.

Novel Inflammatory Markers, Clinical Risk Factors and Virus Type Associated With Severe Respiratory Syncytial Virus Infection

Virus-induced inflammation contributes to respiratory syncytial virus (RSV) pathogenesis. We sought to determine the specific mediators that are associated with more severe illness in young children. Children ≤ 5 years of age seen in our emergency department for respiratory symptoms from September 1998 to May 2008 were eligible for enrollment. Nasopharyngeal wash samples were collected from all eligible patients, and clinical data were recorded. Individuals were included in this study if nasopharyngeal wash samples were positive for RSV only. Patients enrolled in the study were stratified by disease severity, defined as mild (not hospitalized), moderate (hospitalized) or severe (requiring intensive care unit stay). Concentrations of individual inflammatory biomarkers in nasopharyngeal wash fluids were determined using the Luminex human 30-plex assay. Eight hundred fifty-one patients met study criteria: 268 (31.5%) with mild, 503 (59.1%) with moderate and 80 (9.4%) with severe illness. As expected, illness severity was directly associated with young age, prematurity, heart or lung disease, infection with RSV group A and elevated concentrations of interleukin (IL)-2R, IL-6, CXCL8, tumor necrosis factor-α, interferon-α, CCL3, CCL4 and CCL2. In addition, we report several novel and mechanistically important inflammatory biomarkers of severe RSV disease, including IL-1β, IL1-RA, IL-7, epidermal growth factor and hepatocyte growth factor. In a large, longitudinal study (10 years, 851 enrolled patients) limited to RSV infection only, in which well-known risk factors are confirmed, we identified 5 novel biomarkers specifically of severe disease. These markers may ultimately serve to elucidate disease mechanisms.

Association Between Inflammatory Components and Physical Function in the Health, Aging, and Body Composition Study: A Principal Component Analysis Approach

In older adults, studies demonstrate an inverse relationship between physical function and individual inflammatory biomarkers. Given that the inflammatory response is a complex system, a combination of biomarkers may increase the strength and consistency of these associations. This study uses principal component analysis to identify inflammatory "component(s)" and evaluates associations between the identified component(s) and measures of physical function. Principal component analysis with a varimax rotation was used to identify two components from eight inflammatory biomarkers measured in 1,269 older persons. The study sample is a subset of the Health, Aging, and Body Composition study. The two components explained 56% of the total variance in the data (34%, component 1 and 22%, component 2). Five markers (tumor necrosis factor-alpha [TNF-alpha], sTNFRI, sTNFRII, interleukin [IL]-6sR, IL-2sR) loaded highest on the first component (TNF-alpha related), whereas three markers (C-reactive protein [CRP], IL-6, plasminogen activator inhibitor-1) loaded highest on the second component (CRP related). After adjusting for age, sex, race, site, sampling indicator, total lean and fat mass, physical activity, smoking, and anti-inflammatory drug use, knee strength and a physical performance battery score were inversely related to the TNF-alpha-related component, but not to the CRP-related component (knee strength: betaTNFalpha = -2.71, p = .002; betaCRP = -0.88, p = .325; physical performance battery score: betaTNFalpha = -0.05, p < .001; betaCRP = -0.02, p = .171). Both components were positively associated with 400-m walk time, inversely associated with grip strength, and not associated with 20-m walking speed. At least two inflammatory components can be identified in an older population, and these components have inconsistent associations with different aspects of physical performance.

Vitamin K and Vitamin D Status: Associations with Inflammatory Markers in the Framingham Offspring Study

In vitro data suggest protective roles for vitamins K and D in inflammation. To examine associations between vitamins K and D and inflammation in vivo, the authors used multiple linear regression analyses, adjusted for age, sex, body mass index, triglyceride concentrations, use of aspirin, use of lipid-lowering medication, season, menopausal status, and hormone replacement therapy. Participants were from the Framingham Offspring Study (1997-2001; n = 1,381; mean age = 59 years; 52% women). Vitamin K status, measured by plasma phylloquinone concentration and phylloquinone intake, was inversely associated with circulating inflammatory markers as a group and with several individual inflammatory biomarkers (p < 0.01). Percentage of undercarboxylated osteocalcin, a functional measure of vitamin K status, was not associated with overall inflammation but was associated with C-reactive protein (p < 0.01). Although plasma 25-hydroxyvitamin D was inversely associated with urinary isoprostane concentration, an indicator of oxidative stress (p < 0.01), overall associations between vitamin D status and inflammation were inconsistent. The observation that high vitamin K status was associated with lower concentrations of inflammatory markers suggests that a possible protective role for vitamin K in inflammation merits further investigation.