Serologic Response to the Epstein-Barr Virus Peptidome and the Risk for Multiple Sclerosis.

Importance: It remains unclear why only a small proportion of individuals infected with the Epstein-Barr virus (EBV) develop multiple sclerosis (MS) and what the underlying mechanisms are. Objective: To assess the serologic response to all EBV peptides before the first symptoms of MS occur, determine whether the disease is associated with a distinct immune response to EBV, and evaluate whether specific EBV epitopes drive this response. Design, Setting, and Participants: In this prospective, nested case-control study, individuals were selected among US military personnel with serum samples stored in the US Department of Defense Serum Repository. Individuals with MS had serum collected at a median 1 year before onset (reported to the military in 2000-2011) and were matched to controls for age, sex, race and ethnicity, blood collection, and military branch. No individuals were excluded. The data were analyzed between September 1, 2022, and August 31, 2023. Exposure: Antibodies (enrichment z scores) to the human virome measured using VirScan (phage-displayed immunoprecipitation and sequencing). Main Outcome and Measure: Rate ratios (RRs) for MS for antibodies to 2263 EBV peptides (the EBV peptidome) were estimated using conditional logistic regression, adjusting for total anti-EBV nuclear antigen 1 (EBNA-1) antibodies, which have consistently been associated with a higher MS risk. The role of antibodies against other viral peptides was also explored. Results: A total of 30 individuals with MS were matched with 30 controls. Mean (SD) age at sample collection was 27.8 (6.5) years; 46 of 60 participants (76.7%) were male. The antibody response to the EBV peptidome was stronger in individuals with MS, but without a discernible pattern. The antibody responses to 66 EBV peptides, the majority mapping to EBNA antigens, were significantly higher in preonset sera from individuals with MS (RR of highest vs lowest tertile of antibody enrichment, 33.4; 95% CI, 2.5-448.4; P for trend = .008). Higher total anti-EBNA-1 antibodies were also associated with an elevated MS risk (top vs bottom tertile: RR, 27.6; 95% CI, 2.3-327.6; P for trend = .008). After adjusting for total anti-EBNA-1 antibodies, risk estimates from most EBV peptides analyses were attenuated, with 4 remaining significantly associated with MS, the strongest within EBNA-6/EBNA-3C, while the association between total anti-EBNA-1 antibodies and MS persisted. Conclusion and Relevance: These findings suggest that antibody response to EBNA-1 may be the strongest serologic risk factor for MS. No single EBV peptide stood out as being selectively targeted in individuals with MS but not controls. Larger investigations are needed to explore possible heterogeneity of anti-EBV humoral immunity in MS.

Smoking and multiple sclerosis risk in black people: A nested case-control study.

BACKGROUND: Smoking is a well-established risk factor for MS; however, it is not known whether its effect on disease risk varies by race/ethnicity. METHODS: We conducted a nested case-control study among US military personnel who have serum samples stored at the Department of Defense Serum Repository. We measured serum cotinine levels, a marker of tobacco smoke exposure, in 157 Black and 23 White individuals who developed MS during follow-up. Controls were randomly selected and matched to each case by age, sex, race/ethnicity, dates of sample collection, and branch of military service. RESULTS: Smoking was not associated with an increased risk of MS in Black people (RR: 1.08, 95 % CI: 0.63-1.85). The results remained similar in analyses restricted to smoking status at baseline, to samples collected 5 years before symptom onset, and using different cut-off levels in cotinine to define smoking status. Smoking was not statistically significantly associated with MS risk in White people, but the point estimate was similar to what has previously been reported in other studies (RR: 1.85, 95 % CI: 0.56-6.16). CONCLUSIONS: Smoking was not associated with MS risk in Black people. Given the consistent association between smoking and MS risk in predominantly White populations, this may suggest that the association between smoking and MS varies by race/ethnicity.

Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system of unknown etiology. We tested the hypothesis that MS is caused by Epstein-Barr virus (EBV) in a cohort comprising more than 10 million young adults on active duty in the US military, 955 of whom were diagnosed with MS during their period of service. Risk of MS increased 32-fold after infection with EBV but was not increased after infection with other viruses, including the similarly transmitted cytomegalovirus. Serum levels of neurofilament light chain, a biomarker of neuroaxonal degeneration, increased only after EBV seroconversion. These findings cannot be explained by any known risk factor for MS and suggest EBV as the leading cause of MS.

Recommendations for Population-Based Applications of the Adverse Childhood Experiences Study: Position Statement by the American College of Preventive Medicine.

Introduction: Childhood adversity profoundly influences health, well-being, and longevity. Prevention and interventions to mitigate its harmful effects are essential. The American College of Preventive Medicine reviewed the research literature and other professional and governmental statements about adverse childhood experiences to support the development of evidence-based and population-focused recommendations about prevention, screening, and mitigation interventions for childhood adversity. Methods: We performed an umbrella review to find, assess and synthesize the evidence from systematic reviews focused on 3 key questions: the prevention or mitigation of the effects of adverse childhood experiences; the association of screening for adverse childhood experiences with various benefits, including health outcomes; and the effectiveness and harms of interventions in individuals with elevated adverse childhood experience scores. Adverse childhood experience‒related recommendations from 6 professional and governmental organizations were also reviewed. On the basis of these reviews, the American College of Preventive Medicine developed a position statement through consensus. Results: A total of 8 systematic reviews, including 260 studies in total, were identified and combined with adverse childhood experiences‒related recommendations from 6 professional organizations to support the American College of Preventive Medicine recommendations. The American College of Preventive Medicine offers 7 adverse childhood experiences‒related recommendations focused on screening, education/training, policy/practice, and research: 2 are evidence-based, and 5 are based on expert opinion. Notably, regarding secondary prevention of adverse childhood experiences, the American College of Preventive Medicine endorses population-level surveillance and research around childhood adversity but not adverse childhood experience screening in individual clinical encounters. Conclusions: Despite limitations in the heterogeneity and quality of the published systematic reviews, the extant literature supports the American College of Preventive Medicine recommendations. Interventions to enhance protective factors and prevent and mitigate the consequences of adverse childhood experiences and other childhood adversity are promising and require further implementation and research.

The Risk of Pregnancy Related Hypertension Disorder Associated with Sickle Cell Trait in U.S. Service Women.

INTRODUCTION: The health impact of the heterozygous (Hb Ss) Sickle Cell Trait (SCT) among the estimated one million females of reproductive age in the United States on pregnancy related hypertensive disorders (PRHD) including preeclampsia is not as well understood or researched as Sickle Cell Disease (SCD). MATERIALS AND METHODS: This retrospective cohort study included 25,020 U.S. enlisted, active duty service women during 1992 to 2013. Race within the sample is primarily black (84%) given that blacks have the highest prevalence of SCT. All 5,004 SCT positive individuals and a matched sample of 20,016 from those considered SCT negative were followed while on active duty for PRHD outcomes including gestational hypertension (GHTN), preeclampsia and eclampsia. RESULTS: The adjusted incidence rate ratio (IRR) for any PRHD in SCT positive compared to negative individuals was 1.46 (95% CI 1.32 - 1.62). SCT positive versus negative subjects had higher health care utilization rates and utilization rate ratios (URR) for all PRHD diagnoses combined 2.03 (95%CI: 1.97 - 2.10) and for each specific PHRD diagnosis. The prevalence of preeclampsia or eclampsia did not vary by SCT status. The overall PRHD attributable risk due to SCT was 30.4% (95% CI 23.1-37.1%) and the overall number needed to screen to detect a case of PRHD was 156 (95% CI 117-220). CONCLUSIONS: The results of this study indicate that being SCT positive is a risk factor for PRHD and provides evidence that SCT status may have an adverse effect on reproductive health. Future research needs to include other known risk factors for PRHD to include gravity and parity history, BMI, past history of PRHD prior to enlistment as well as to examine the association with maternal/child pregnancy outcomes.

Severe Upper Limb Injuries in U.S. Military Personnel: Incidence, Risk Factor and Outcomes.

BACKGROUND: Severe upper limb injuries (SULI) may pose a significant public health challenge for the military; however, SULI has not been previously defined or studied in the US military. Objective: Determine SULI incidence, risk factors, and outcomes. MATERIALS AND METHODS: Active Component (AC) U.S. military personnel who served during January 1, 2003 to December 31, 2012 who met the case definition for SULI (N = 213,745) and a random sample from the same population without SULI were included. Data from the Defense Medical Surveillance System and Defense Medical Epidemiology Database was used to calculate incidence. Multiple logistic regression and Cox proportional hazards models were used to analyze SULI risk factors and attrition. RESULTS: SULI incidence was 15/1,000 person-years. Higher SULI risk was observed in men (OR 1.25; 95% CI 1.22-1.27), age 25-29 (OR 1.07; 95% CI 1.05-1.09) compared to age 20-24, E5-E9 (OR 1.14; 95% CI 1.12-1.17) compared to E1-E4, serving in Coast guard (OR 1.62; 95% CI 1.56-1.68) and Air Force (OR 1.17; 95% CI 1.14-1.19) relative to Army and with a deployment history (OR 2.16, 95% CI 2.12-2.19) while SULI risk was lower for blacks (OR 0.91; 95% CI 0.90-0.93) and those in the "other race" category (HR 0.81; 95% CI 0.80-0.84) compared to whites. SULI was associated with 23% increased risk of attrition (HR 1.23; 95% CI 1.22-1.24). CONCLUSION: The study findings provide preliminary evidence on the incidence, natural history and distribution of SULI in this population. The findings indicate SULI may impact readiness and result in premature military separation.

Serum Neurofilament Light Chain Levels in Patients With Presymptomatic Multiple Sclerosis.

Importance: Unrecognized demyelinating events often precede the clinical onset of multiple sclerosis (MS). Identification of these events at the time of occurrence would have implications for early diagnosis and the search of causal factors for the disease. Objective: To assess whether serum neurofilament light chain (sNfL) levels are elevated before the clinical MS onset. Design, Setting, and Participants: Nested case-control study among US military personnel who have serum samples stored in the US Department of Defense Serum Repository. Serum samples were collected from 2000 to 2011; sNfL assays and data analyses were performed from 2018 to 2019. We selected 60 case patients with MS who either had 2 samples collected before onset (mean follow-up, 6.3 years) or 1 sample collected before and 1 after onset (mean follow-up, 1.3 years), among 245 previously identified case patients. For each case, we randomly selected 1 of 2 previously identified control individuals matched by age, sex, race/ethnicity, and dates of sample collection. The sample size was chosen based on the available funding. Exposures: Serum NfL concentrations measured using an ultrasensitive single-molecule array assay (Simoa). Main Outcomes and Measurements: Log-transformed sNfL concentrations in case patients and control individuals compared using conditional logistic regression and linear mixed models. Results: Mean age at baseline was 27.5 years, and 92 of 120 participants (76.7%) were men. Serum NfL levels were higher in case patients with MS compared with their matched control individuals in samples drawn a median of 6 years (range, 4-10 years) before the clinical onset (median, 16.7 pg/mL; interquartile range [IQR], 12.6-23.1 pg/mL vs 15.2 pg/m; IQR, 10.3-19.9 pg/mL; P = .04). This difference increased with decreasing time to the case clinical onset (estimated coefficient for interaction with time = 0.063; P = .008). A within-person increase in presymptomatic sNfL levels was associated with higher MS risk (rate ratio for ≥5 pg/mL increase, 7.50; 95% CI, 1.72-32.80). The clinical onset was associated with a marked increase in sNfL levels (median, 25.0; IQR, 17.1-41.3 vs 45.1; IQR, 27.0-102.7 pg/mL for presymptomatic and postonset MS samples; P = .009). Conclusions and Relevance: The levels of sNfL were increased 6 years before the clinical MS onset, indicating that MS may have a prodromal phase lasting several years and that neuroaxonal damage occurs already during this phase.

Electronic Nicotine Delivery Systems or E-cigarettes: American College of Preventive Medicine's Practice Statement.

INTRODUCTION: E-cigarettes or or electronic nicotine delivery systems (ENDS) have rapidly gained popularity in the U.S. Controversy exists about the safety and efficacy of ENDS. The American College of Preventive Medicine's Prevention Practice Committee undertook a consensus-based evidence review process to develop a practice statement for the American College of Preventive Medicine. METHODS: A rapid review of the literature was performed through June 2017 to identify efficacy, patient-oriented harms, and the impact on population health. RESULTS: On an individual level, limited evidence suggests that ENDS may be effective at reducing cigarette use among adult smokers intending to quit. There is insufficient evidence addressing potential long-term harms of ENDS, and limited evidence is available about short-term harms of ENDS and the impact of secondhand exposure. Although ENDS appear safer than combustible cigarettes, they are not without risk. Among youth there is no known benefit and significant concern for harm. On a population level, there may be significant harms associated with ENDS, particularly among youth nonsmokers. The long-term balance of potential benefits versus harms from the individual and population perspectives are unclear. CONCLUSIONS: The American College of Preventive Medicine developed practice recommendations that include encouraging screening for ENDS use, strategies to prevent the initiation of ENDS use in nonsmokers, particularly in youth, adoption of a harm reduction model for smokers intending to quit in those who refuse or fail to quit with evidence-based smoking-cessation methods, recommendations on policy and regulatory strategies to decrease public use of ENDS and regulation of their components, and future research needs.

Association Between Sickle Cell Trait With Selected Chronic Medical Conditions in U.S. Service Members.

Introduction: Sickle cell trait (SCT), the heterozygous carrier state for hemoglobin S, is present in an estimated 1.6% of all newborns and 7.3% in black individuals in the USA. SCT has long been considered a benign condition with anticipated normal life expectancy and no increased risk for chronic diseases. The medical literature is inconclusive on the potential association between SCT and chronic medical conditions (CMC) including chronic kidney disease, venous thromboembolism, and stroke. Studies addressing these questions are lacking particularly in non-Black young adults. Materials and Methods: We conducted a retrospective cohort study among U.S. active duty, enlisted, service members who entered from 1992 to 2012 using existing Department of Defense (DoD Military Healthcare System databases). SCT positive subjects (1,323) were matched by demographic characteristics to SCT negative subjects (3,136) and followed through 2013 for CMC that included deep vein thrombosis, diabetes mellitus and hematologic, pulmonary, and renal conditions. Results: The rate of developing any of the included CMC was higher for those with SCT (incidence rate ratio = 1.71 95% CI 1.61-1.81) compared with those who were SCT negative and their healthcare utilization rate for any of CMC studied was higher for SCT positive compared with negative individuals (URR = 2.45 95% CI 2.41-2.50), with the highest rate ratios observed for hematologic and renal conditions. SCT positive compared with negative individuals were more likely to have encounter diagnoses of sickle cell disease and diabetes Type II and were less likely to have encounter diagnoses of other hemoglobinopathies and diabetes type I. Conclusion: SCT in these racially diverse, young adults increased both the incidence of and healthcare utilization for thromboembolism, diabetes mellitus type II, sickle cell disease, pulmonary, and chronic renal conditions. These findings suggest that clinicians treating young adults with SCT should exercise heightened surveillance for these CMC to ensure both early diagnosis and access to treatments.

The Association Between Sickle Cell Trait in U.S. Service Members with Deployment, Length of Service, and Mortality, 1992-2012.

Introduction: Sickle cell trait (SCT) affects an estimated 5.02% of non-Hispanic blacks, 1.08% of Hispanics, and 0.1% of Whites in the U.S. military. Policies for SCT screening and occupational restrictions vary by service. Population-based studies of SCT with quantification of military-relevant outcomes are lacking. Methods: The study design was a retrospective cohort of 15,081 SCT-positive versus 60,320 SCT-negative U.S. active duty personnel enlisted from 1992 to 2012 and followed through 2013. Military-relevant outcome included number and days of deployment, length of service, and cause of death. Results: SCT-positive versus SCT-negative service members experienced more deployments (p < 0.01) and longer number of days deployed for all services, especially the Army (p < 0.001). The median length of service was longer for SCT-positive service members stratified by service and by gender (p < 0.05). The adjusted risk of length of service greater than 5 yr by SCT status was 1.37 (95% confidence interval 1.31-1.43) with greater than a three-fold higher risk in the Navy and Air Force compared with the Army. Crude mortality rate was not significantly different by SCT status, although deaths due to suicide, self-directed violence, and other non-specific causes were more common in SCT-positive service members. Conclusion: We found that SCT-positive service members deployed more frequently, for greater lengths of time, and remained in service longer. No significant difference in crude mortality ratio was discovered. Additional research on military-relevant outcomes and a cost-effectiveness analysis of SCT screening practices are needed to inform evidence-based SCT enlistment policies.

Risk of Exertional Heat Illnesses Associated with Sickle Cell Trait in U.S. Military.

Introduction: A number of studies have found an association between sickle cell trait (SCT) and exertional heat illnesses (EHIs) including heat stroke, a potentially fatal condition. The strength of this association varied across studies, limiting the ability to quantify potential benefits of SCT-screening policies for competitive athletics and military service members. We determined the relative rate and attributable risk of developing EHI associated with being SCT positive and the EHI health care utilization. Methods: We conducted a retrospective cohort study among U.S. enlisted, active duty service members during 1992-2012 from the Department of Defense Military Healthcare System databases. All 15,081 SCT-positive individuals and a sample of 60,320 from those considered SCT negative were followed through 2013 for EHI outcomes ranging from mild heat illness to heat stroke. Results: The adjusted hazard ratio for EHI in SCT-positive compared with SCT-negative individuals was 1.24 (95% confidence interval 1.06, 1.45). Risk factors for EHI included age over 30 yr at enlistment, female gender, Marine Corps, combat occupations, and enlistment between April and June. An estimated 216 Department of Defense enlistees (95% confidence interval: 147, 370) would need to be screened to identify and potentially prevent one case of EHI. The attributable risk of EHI due to SCT was 33% (95% confidence interval 19, 45%). Conclusion: Our findings suggest that SCT screening will identify approximately a third of SCT individuals at risk for EHI, but does not provide definitive evidence for universal compared with selective (e.g., occupational based) in military enlistees. A cost-effectiveness analysis is needed for policy makers to assess the overall value of universal SCT screening to prevent morbidity and mortality in both the military and the collegiate athletic populations.

Monocyte activation detected prior to a diagnosis of schizophrenia in the US Military New Onset Psychosis Project (MNOPP).

Low-grade inflammation is present in some cases of schizophrenia, particularly in the early stages of this disorder. The inflammation source is not known but may be the result of dysbiotic processes occurring in the gut. We examined peripheral biomarkers of bacterial translocation, soluble CD14 (sCD14) and lipopolysaccharide binding protein (LBP), and of general inflammation, C-reactive protein (CRP), in a unique, pre-onset study of schizophrenia. This sample was composed of 80 case-control matched pairs of US military service members from whom blood samples were obtained at time of entry to service, before a psychiatric diagnosis was made. Elevated levels of sCD14 in individuals who were subsequently diagnosed with schizophrenia generated odds ratios of 1.22 for association with disease (p<0.02). Conversely, LBP levels for those who developed schizophrenia were unchanged or very marginally decreased compared to controls (p=0.06). No significant changes were found for CRP in schizophrenia compared with their matched controls. This diversity of patterns suggests that a dysregulated immune system is present prior to a diagnosis of schizophrenia. In particular, sCD14 elevation and discordant LBP decrease in cases support a more generalized monocyte activation rather than a specific translocation of gut bacteria into circulation. The corresponding absence of general inflammation as measured by CRP may indicate that this monocyte activation or related immune dysfunction precedes the early inflammatory stage frequently evident in schizophrenia.

Sickle Cell Trait Prevalence Among U.S. Military Service Members: 1992-2012.

BACKGROUND: Population-based estimates of sickle cell trait (SCT) prevalence in the U.S. military across services and over time are lacking. METHODS: SCT prevalence by service, race/ethnicity, and gender in 5-year time intervals was estimated using demographic, ambulatory, and hospital SCT encounter (International Classification of Diseases, 9th Revision, Clinical Modification 282.5) data for active duty, enlisted between 1992 and 2012 and limited SCT laboratory results. RESULTS: Our study identified 15,081 SCT subjects. SCT prevalence varied significantly by race, year, gender, and service branch. SCT prevalence was highest for non-Hispanic blacks (5.02%; prevalence ratio = 56.33, confidence interval [CI] = 52.14-60.85; compared to non-Hispanic white) in 2005-2009 (0.40%; prevalence ratio = 10.04, CI = 9.21-10.94; compared to 1992-1994), for women (2.97%; prevalence ratio = 3.14, CI = 3.04-3.25; compared to men), and in the Navy (2.26%; prevalence ratio = 2.96, CI = 2.84-3.02; compared to Army). Among foreign born, Africans were more likely to be SCT+ (prevalence ratio = 1.68, CI = 1.39-2.04; compared to non-U.S. North American). CONCLUSION: This study estimated the prevalence of SCT within U.S. military enlisted force and describes variability across services for race, time intervals, gender, and foreign-born region and will support investigation into the health effects of SCT in young adult populations.

The Relationship Between Enlistment Body Mass Index and the Development of Obstructive Sleep Apnea in the U.S. Military.

BACKGROUND: The incidence of obstructive sleep apnea (OSA) in the military has risen dramatically. OSA is considered "service connected" and compensable by the Veterans Administration. The association between body mass index (BMI) (kg/m(2)) measured at initial enlistment and development of OSA has yet to be assessed. METHODS: Data were obtained from the Defense Medical Surveillance System, the Armed Forces Health Surveillance Center, U.S. Department of Defense, Silver Spring, Maryland (inclusive dates:1993-2012; release date: December 2013). A study population of 550,000 randomly-selected active duty enlisted personnel was followed retrospectively from January 1, 2008, through December 31, 2012, or until diagnosis with OSA, separation from the military, or death occurred. The main exposure of interest was BMI recorded at time of enlistment. RESULTS: Adjusted hazard ratios for enlistment BMI were calculated using BMI of 23 to 23.9 as reference. Exponentially increasing risk for OSA was observed as BMI increased. The heaviest individuals (BMI > 35) were at the highest risk (hazard ratio: 3.93; 95% confidence interval [CI]: 3.35-4.62) for developing OSA. CONCLUSION: Enlistment BMI's role in developing OSA may be valuable in designing screening tools and preventive interventions in higher-risk groups, as well as prompt further consideration in the realm of military enlistment policy.

The American College of Preventive Medicine Position Statement on Hepatitis C Virus Infection.

The American College of Preventive Medicine Prevention Practice Committee contributes to policy guidelines and recommendations on preventive health topics for clinicians and public health decision makers. After review of the currently available evidence, the College is providing a consensus-based set of recommendations designed to increase screening for and prevention of hepatitis C virus infection, increase linkage to care, improve access to treatment, and encourage development of hepatitis C virus-related quality measures.

Towards a blood-based diagnostic panel for bipolar disorder.

BACKGROUND: Bipolar disorder (BD) is a costly, devastating and life shortening mental disorder that is often misdiagnosed, especially on initial presentation. Misdiagnosis frequently results in ineffective treatment. We investigated the utility of a biomarker panel as a diagnostic test for BD. METHODS AND FINDINGS: We performed a meta-analysis of eight case-control studies to define a diagnostic biomarker panel for BD. After validating the panel on established BD patients, we applied it to undiagnosed BD patients. We analysed 249 BD, 122 pre-diagnostic BD, 75 pre-diagnostic schizophrenia and 90 first onset major depression disorder (MDD) patients and 371 controls. The biomarker panel was identified using ten-fold cross-validation with lasso regression applied to the 87 analytes available across the meta-analysis studies. We identified 20 protein analytes with excellent predictive performance [area under the curve (AUC)⩾0.90]. Importantly, the panel had a good predictive performance (AUC 0.84) to differentiate 12 misdiagnosed BD patients from 90 first onset MDD patients, and a fair to good predictive performance (AUC 0.79) to differentiate between 110 pre-diagnostic BD patients and 184 controls. We also demonstrated the disease specificity of the panel. CONCLUSIONS: An early and accurate diagnosis has the potential to delay or even prevent the onset of BD. This study demonstrates the potential utility of a biomarker panel as a diagnostic test for BD.

Biomarker identification and effect estimation on schizophrenia - a high dimensional data analysis.

Biomarkers have been examined in schizophrenia research for decades. Medical morbidity and mortality rates, as well as personal and societal costs, are associated with schizophrenia patients. The identification of biomarkers and alleles, which often have a small effect individually, may help to develop new diagnostic tests for early identification and treatment. Currently, there is not a commonly accepted statistical approach to identify predictive biomarkers from high dimensional data. We used space decomposition-gradient-regression (DGR) method to select biomarkers, which are associated with the risk of schizophrenia. Then, we used the gradient scores, generated from the selected biomarkers, as the prediction factor in regression to estimate their effects. We also used an alternative approach, classification and regression tree, to compare the biomarker selected by DGR and found about 70% of the selected biomarkers were the same. However, the advantage of DGR is that it can evaluate individual effects for each biomarker from their combined effect. In DGR analysis of serum specimens of US military service members with a diagnosis of schizophrenia from 1992 to 2005 and their controls, Alpha-1-Antitrypsin (AAT), Interleukin-6 receptor (IL-6r) and connective tissue growth factor were selected to identify schizophrenia for males; and AAT, Apolipoprotein B and Sortilin were selected for females. If these findings from military subjects are replicated by other studies, they suggest the possibility of a novel biomarker panel as an adjunct to earlier diagnosis and initiation of treatment.

Predictors of the Onset of Schizophrenia in US Military Personnel.

Alterations in immune response may be an important component in the etiopathogenesis of schizophrenia and bipolar disorder. We examined the associations of pentraxin-3 (PTX3) with the onset of schizophrenia or bipolar disorder. We tested preonset serum specimens from 160 US military service members who were later diagnosed with schizophrenia or bipolar disorder and 160 matched controls without psychiatric disorders. Lower serum levels of PTX3 were predictive of schizophrenia but not of bipolar disorder. Subjects with below-median PTX3 levels had a 3.0 odds ratio (confidence interval, 1.6-5.7) for schizophrenia onset in the multivariable logistic regression model controlling for demographic and military variables. The test for trends was significant (p = 0.002), with the likelihood increasing as the levels of PTX3 decreased. Crude and adjusted categorized levels were not predictive of bipolar disorder. A lower level of inflammatory response indicated by PTX3 might be implicated in developing schizophrenia.