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.

Epidemiology of Major Depressive Disorder Disability in the US Military: FY 2007-2012.

This study assesses the incidence of major depressive disorder (MDD) disability discharge and retirement in the Army, Navy, Marine Corps and Air Force and describes MDD comorbidity. Service members with a disability discharge for either MDD (n = 2,882) or any nonpsychiatric disability (n = 56,145), between fiscal years 2007 and 2012, were included in the study population. Those with MDD disability at first evaluation but not at last evaluation were excluded. The incidence of MDD disability discharge increased significantly in the Army and Air Force between fiscal years 2007 and 2012. MDD disability retirement significantly increased in the Army, Navy, and Air Force. Females, and those who experienced at least one deployment, had higher incidence rates of MDD disability discharge. All services included spinal diseases and posttraumatic stress disorder in their top five comorbid categories. Given the association between trauma and MDD, further research into the role of both combat exposure and injury on MDD is merited.

Meta-analysis of Cigarette Smoking and Musculoskeletal Injuries in Military Training.

PURPOSE: Tobacco use is common among military personnel, as is musculoskeletal injury during training. In a review of the literature on musculoskeletal injuries, there was mixed evidence on the role of smoking as a risk factor. The purpose of this study is to review and analyze the literature on the impact of cigarette smoking on lower-extremity overuse injuries in military training. METHODS: We performed a literature search on articles published through October 2016. Search terms focused on lower-extremity overuse musculoskeletal injuries and cigarette smoking in military populations. We conducted a meta-analysis overall and by sex, including smoking intensity. RESULTS: We identified 129 potential studies and selected 18 based on quality. The overall rate ratio for smoking was 1.31, 1.31 for men, and 1.23 for women. Overall and for each sex, rate ratios were significantly greater than 1.0 for each intensity level of smoking. CONCLUSIONS: Smoking is a moderate risk factor for musculoskeletal injury and may account for a meaningful proportion of injuries among men and women due to the high prevalence of smoking and injury in this population. Although enlistees are not allowed to smoke during basic training, their risk of injury remains high, indicating that smokers may remain at increased risk for medium- to long-term duration.

Preenlistment and Early Service Risk Factors for Traumatic Brain Injury in the Army and Marine Corps: FY 2002-2010.

OBJECTIVE: To determine the preenlistment and early service risk factors for traumatic brain injury (TBI)-related disability in Army and Marine Corps service members. DESIGN: Matched case-control design. MAIN OUTCOME: TBI disability discharges. SUBJECTS: Army and Marine Corps service members with an enlistment record and disability discharge for TBI were included as cases. Controls were selected from the enlisted population with no disability evaluation record and were matched on fiscal year of enlistment, sex, and service at a ratio of 5:1. RESULTS: Older age at enlistment resulted in a significantly increased risk for TBI disability in the crude and adjusted models (adjusted odds ratio [aOR] = 1.49; 95% confidence interval [CI], 1.16-1.91). An enlistment military occupational specialty (MOS) with a combat arms designation resulted in an almost 3-fold increased odds of TBI disability compared with other MOS categories (aOR = 2.75; 95% CI, 2.46-3.09). This remained a significant risk factor for TBI disability in the multivariate model (aOR = 2.74; 95% CI, 2.45-3.08). CONCLUSION: Results from this study help inform the existing body of military TBI research by highlighting the preenlistment demographic and early service risk factors for TBI disability. Further research into the role of age on TBI disability in the military is merited.

Excess Stress Fractures, Musculoskeletal Injuries, and Health Care Utilization Among Unfit and Overweight Female Army Trainees.

BACKGROUND: Musculoskeletal injuries are prevalent among military trainees and certain occupations. Fitness and body mass index (BMI) have been associated with musculoskeletal conditions, including stress fractures. HYPOTHESIS: The incidence of, and excess health care utilization for, stress fracture and non-stress fracture overuse musculoskeletal injuries during the first 6 months of service is higher among unfit female recruits. Those who exceeded body fat limits are at a greater risk of incident stress fractures, injuries, or health care utilization compared with weight-qualified recruits. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: All applicants to the United States Army were required to take a preaccession fitness test during the study period (February 2005-September 2006). The test included a 5-minute step test scored as pass or fail. BMI was recorded at application. There were 2 distinct comparisons made in this study: (1) between weight-qualified physically fit and unfit women and (2) between weight-qualified physically fit women and those who exceeded body fat limits. We compared the incidence of, and excess health care utilization for, musculoskeletal injuries, including stress fractures and physical therapy visits, during the first 183 days of military service. RESULTS: Among the weight-qualified women, unfit participants had a higher non-stress fracture injury incidence and related excess health care utilization rate compared with fit women, with rate ratios of 1.32 (95% CI, 1.14-1.53) and 1.18 (95% CI, 1.10-1.27), respectively. Among fit women, compared with the weight-qualified participants, those exceeding body fat limits had higher rate ratios for non-stress fracture injury incidence and related excess health care utilization of 1.27 (95% CI, 1.07-1.50) and 1.20 (95% CI, 1.11-1.31), respectively. Weight-qualified women who were unfit had a higher incidence of stress fractures and related excess health care utilization compared with fit women, with rate ratios of 1.62 (95% CI, 1.19-2.21) and 1.22 (95% CI, 1.10-1.36), respectively. Among fit women exceeding body fat limits, the stress fracture incidence and related excess health care utilization rate ratios were 0.79 (95% CI, 0.49-1.28) and 1.44 (95% CI, 1.20-1.72), respectively, compared with those who were weight qualified. CONCLUSION: The results indicate a significantly increased risk of musculoskeletal injuries, including stress fractures, among unfit recruits and an increased risk of non-stress fracture musculoskeletal injuries among recruits who exceeded body fat limits. Once injured, female recruits who were weight qualified but unfit and those who were fit but exceeded body fat limits had increased health care utilization. These findings may have implications for military accession and training policies as downsizing of military services will make it more important than ever to optimize the health and performance of individual service members.

Non-Cognitive Personality Assessment and Risk of Injuries Among Army Trainees.

INTRODUCTION: Low levels of pre-accession physical fitness and activity are risk factors for stress fractures and other overuse musculoskeletal injuries among military trainees. One dimension in the Tailored Adaptive Personality Assessment System (TAPAS), a non-cognitive personality test given to Army applicants, specifically assesses propensity to engage in physical activity. This dimension may serve as a surrogate measure for activity or fitness. The study examines the associations between TAPAS dimension scores and risk of musculoskeletal injuries. METHODS: Fifteen TAPAS dimension scores for 15,082 U.S. Army trainees entering military service in 2010 were provided by the U.S. Army Research Institute for Social and Behavioral Sciences. During 2013-2015, the associations between TAPAS dimension scores (as a continuous variable) and injuries in the first 6 months of service were evaluated using logistic regression, with the measure of association being the OR. RESULTS: The TAPAS physical conditioning dimension was associated with musculoskeletal injuries and stress fractures among both men (musculoskeletal injury, OR=0.83, 95% CI=0.79, 0.86; stress fracture, OR=0.68, 95% CI=0.57, 0.80) and women (musculoskeletal injury, OR=0.77, 95% CI=0.70, 0.85; stress fracture, OR=0.60, 95% CI=0.43, 082). No other dimensions were both significantly and consistently associated with either injury. CONCLUSIONS: The TAPAS physical conditioning dimension is a strong predictor of musculoskeletal injury and stress fracture among male and female U.S. Army trainees, and may serve as a pre-accession screen for self-reported physical activity.

The Relationship Between Deployment Frequency and Cumulative Duration, and Discharge for Disability Retirement Among Enlisted Active Duty Soldiers and Marines.

BACKGROUND: The frequency and duration of deployments associated with increased morbidity is a significant concern for force health protection within the military population. Understanding the association between deployment and disability may provide a clearer understanding of factors adversely affecting U.S. military force readiness. METHODS: A case-control analysis was conducted using records on enlisted active duty personnel in the Army and Marine Corps who were evaluated for a musculoskeletal disability and received a final disability disposition between FY 2003 and 2012. The study compared deployment, deployment frequency, and total time deployed in personnel who received musculoskeletal disability retirement to those with a musculoskeletal disability discharge other than retirement. RESULTS: For females and males in either service, any deployment was associated with an increased risk of disability retirement (adjusted odds ratios [aOR] [95% confidence intervals (CI)]: males 1.76 [1.65-1.87]; females 1.41 [1.21-1.64]). Furthermore, increasing number of deployments (3+ deployments males aOR [95% CI]: 2.21 [1.92-2.53]) and time spent deployed (24+ months Army Males aOR [95% CI]: 2.07 [1.79-2.40]) significantly increased the odds for disability retirement. CONCLUSION: Increasing frequency and duration of military deployments has an increased risk of disability retirement in service members with a musculoskeletal disability. Further research on this relationship is needed in a more representative sample of the U.S. military population.

Epidemiology of asthma-related disability in the U.S. Armed Forces: 2007-2012.

OBJECTIVE: To characterize the demographic, disability and deployment characteristics of U.S. Armed Forces personnel with an asthma-related disability discharge, which includes separation (without benefits) and retirement (with disability benefits). METHODS: Incidence rates for personnel evaluated for disability discharge and/or disability retired due to asthma and due to all other causes of disability discharge were calculated per 100,000 active duty enlisted service members by year. Multivariate logistical regression was used to examine the associations between disability retirement and several demographic and disability characteristics of service members evaluated for asthma-related disability discharge versus those evaluated for any other non-respiratory condition for each branch of military service. RESULTS: Service members evaluated for disability discharge related to asthma most often do not have comorbidity and are disability retired rather than separated, with rates of disability retirement increasing over time. Groups with a significantly higher incidence of evaluation for asthma-related disability include females, individuals who entered the military prior to the age of 20, non-Whites, and those with a history of deployment to Iraq or Afghanistan. The characteristic most associated with the odds of disability retirement was a history of deployment. CONCLUSIONS: New-onset asthma occurring after military entry often causes occupational impairment in service members, especially in those that have been deployed to Iraq or Afghanistan.

Risk factors for disability discharge in enlisted active duty Army soldiers.

BACKGROUND: The rate of permanent disability retirement in U.S. Army soldiers and the prevalence of combat-related disabilities have significantly increased over time. Prior research on risk factors associated with disability retirement included soldiers retired prior to conflicts in Iraq and Afghanistan. OBJECTIVE: To identify risk factors for disability discharge among soldiers enlisted in the U.S. Army during military operations in Iraq and Afghanistan. METHODS: In this case-control study, cases included active duty soldiers evaluated for disability discharge. Controls, randomly selected from soldiers with no history of disability evaluation, were matched to cases based on enlistment year and sex. Conditional logistic regression models calculated odds of disability discharge. Attributable fractions estimated burden of disability for specific pre-existing condition categories. Poisson regression models compared risk of disability discharge related to common disability types by deployment and combat status. RESULTS: Characteristics at military enlistment with increased odds of disability discharge included a pre-existing condition, increased age or body mass index, white race, and being divorced. Musculoskeletal conditions and overweight contributed the largest proportion of disabilities. Deployment was protective against disability discharge or receiving a musculoskeletal-related disability, but significantly increased the risk of disability related to a psychiatric or neurological condition. CONCLUSIONS: Soldiers with a pre-existing condition at enlistment, particularly a musculoskeletal condition, had increased odds of disability discharge. Risk of disability was dependent on condition category when stratified by deployment and combat status. Additional research examining conditions during pre-disability hospitalizations could provide insight on specific conditions that commonly lead to disability discharge.

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.

Identification of Fall Prevention Strategies for the Military: A Review of the Literature.

UNLABELLED: In the U.S. Army, falls have historically been among the top five causes of hospitalization and a leading cause of nonbattle injuries in military operations overseas. OBJECTIVE: For safety and public health professionals, commanders, and supervisors looking to address this problem, a literature review was conducted to identify and summarize existing fall prevention strategies applicable to a working-age population. METHODS: A total of nine literature databases were searched for articles published from 1970 to 2011. Article titles and abstracts were screened to select original research with an injury or noninjury outcome. Intervention studies were reviewed in detail and quality scored by 3 public health scientists. RESULTS: The search identified over 2,200 articles. Of these, 525 met inclusion criteria and were reviewed in more detail, resulting in identification of 9 interventions. Nearly all of the identified interventions had been implemented in occupational environments. Study quality was rated and scores ranged from 4.5 to 8.0 (maximum 10 points). CONCLUSIONS: Few intervention studies were identified. Multifaceted programs showed the greatest promise for translation to military environments. Additional evaluation research is greatly needed to further efforts to address this leading military public health problem.

Epidemiology of psychiatric disability without posttraumatic stress disorder among U.S. Army and Marine Corps personnel evaluated for disability discharge.

Psychiatric disorders are a common reason for disability discharge from the U.S. military. Research on psychiatric disorders in military personnel evaluated for disability discharge has historically focused on posttraumatic stress disorder (PTSD), yet 40% of service members evaluated for a psychiatric-related disability do not have PTSD. This study's objective was to describe characteristics and correlates of disability in Army and Marine Corps personnel diagnosed with psychiatric disorders other than PTSD. In this cross-sectional study, the chi-square and Wilcoxon-Mann-Whitney tests compared the distribution of demographic, disability and deployment characteristics between those evaluated for non-PTSD psychiatric disability (N = 9125) versus those evaluated for any other non-psychiatric condition (N = 78,072). Multivariate logistic regression examined associations between disability retirement and demographic and disability characteristics. Results show a significantly higher prevalence of disability retirement, deployment, and comorbidity among Army and Marine Corps personnel evaluated for disability discharge related to a non-PTSD psychiatric disorder. Mood disorders, anxiety disorders and dementia were the most commonly evaluated psychiatric disorders. Characteristics associated with increased odds of non-PTSD psychiatric-related disability retirement includes being in the Marine Corps (OR = 1.24), being black (OR = 1.29) or other race (OR = 1.33), having a combat-related condition (OR = 2.50), and older age. Service members evaluated for a non-PTSD psychiatric disability have similar rates of disability retirement as those evaluated for PTSD, suggesting non-PTSD psychiatric disorders cause a severe and highly compensated disability. Additional research is needed describing the epidemiology of specific non-PTSD psychiatric disorders, such as depression, in service members evaluated for disability discharge.

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.

Risk factors for back-related disability in the US Army and Marine Corps.

STUDY DESIGN: Matched case-control epidemiological study. OBJECTIVE: To identify pre-enlistment, demographic, and service-related risk factors for back-related disability in enlisted US soldiers and Marines comparing those who were deployed with those who did not deploy during the service term. SUMMARY OF BACKGROUND DATA: Back conditions are a major cause of morbidity and lost work days in both the US working population and military. Back-related conditions are among the most prevalent causes of military disability discharge but little research has been conducted to identify risk factors for back-related disabilities in this population. METHODS: Cases included enlisted Army and Marine Corps service members evaluated for back-related disability. Controls, frequency matched by year of military entrance and service, were selected from the enlisted service member population. Pre-enlistment demographic and medical characteristics, deployment, and ambulatory care data collected from existing military databases were used. Crude and adjusted odds of back-related disability were modeled using conditional logistic regression. RESULTS: In adjusted models, service members who were overweight (odds ratio [OR]: 1.17; 95% confidence interval [95% CI]: 1.12-1.23) and obese (OR: 1.35; 95% CI: 1.26-1.44), between ages 25 and 29 years (OR: 1.23; 95% CI: 1.16-1.31), or 30 years or older (OR: 1.43; 95% CI: 1.34-1.52) at military entrance were at increased odds of a back-related disability. History of a back diagnosis at the pre-enlistment medical examination (OR: 1.94; 95% CI: 1.50-2.50) and deploying once (OR: 1.09; 95% CI: 1.05-1.14) were also associated with increased odds of a back-related disability. CONCLUSION: Enlisted soldiers and marines with back-related disabilities were more likely to be older, have a higher body mass index, have a history of pre-enlistment back conditions, and were deployed once, compared with controls without a back-related disability. Additional research is necessary to further examine the complex relationship between deployment to combat zones, onset of musculoskeletal symptoms, and back-related disability in soldiers and marines. LEVEL OF EVIDENCE: 4.

Temporal trends in disability evaluation and retirement in the Army, Navy, and Marine Corps: 2005-2011.

BACKGROUND: Surveillance of trends in disability is necessary to determine the burden of disability on the U.S. military, the most common types of disability conditions, and the prevalence of combat exposures in the disability population. Previous studies of disability in the U.S. military have focused on a particular service or condition rather than examining the epidemiology of disability in the military overall. OBJECTIVE: This study's objective is to describe rates of disability evaluation and retirement in U.S. Army, Navy, and Marine Corps. METHODS: A cross-sectional study of 126,170 service members evaluated for disability discharge from the U.S. military in fiscal years 2005-2011 was conducted. Crude and standardized rates of disability evaluation and retirement were calculated per 10,000 service members by year of disability, demographic characteristics, and type of disability evaluation or retirement. Temporal trends in the prevalence of combat-related disability in the disability evaluated and retired population were also examined. RESULTS: Rates of disability evaluation and retirement were highest among female, enlisted, and active duty service members. Overall rates of disability evaluation significantly decreased, while rates of disability retirement increased. Rates of psychiatric disability evaluation and retirement significantly increased in all services during the same time period from 2005 to 2011. Combat-related disability evaluations and retirements have substantially increased in all services particularly among psychiatric disability cases. CONCLUSIONS: Psychiatric disability, combat-related disability, and disability retirement continue to increase in the military, despite observed decreases in the rates of disability the Department of Defense since 2005.

Risk factors for disability retirement among active duty Air Force personnel.

OBJECTIVE: To determine risk factors for disability retirement in Air Force personnel, as well as the conditions contributing to disability retirement. METHODS: A matched case-control study was conducted. Air Force personnel with accession records who were disability retired between 2002 and 2011 were included as cases. Controls were matched by accession year from the population of accessions not evaluated for disability at a ratio of 2:1. Conditional logistic regression was used to determine the odds of disability retirement. RESULTS: Women and those aged 25 or older were significantly more likely to be disability retired. Deployment was also associated with disability retirement but was significantly protective. Among women, the odds of disability retirement did not vary when stratified by deployment history. Preexisting medical conditions were not associated with disability retirement. Psychiatric conditions were the most common condition type among those who were disability retired in the Air Force. CONCLUSIONS: Additional studies are needed to assess risk factors for psychiatric disability, the most common disability retired condition, as well as to describe the role of occupation and combat exposure in disability retirement from the Air Force.

Trends in the epidemiology of disability related to traumatic brain injury in the US Army and Marine Corps: 2005 to 2010.

BACKGROUND: Traumatic brain injury (TBI) has been recognized as a major public health issue for several decades. Despite technological advancements in protective equipment and medical care available during recent military conflicts, TBI is the most common neurological condition among Soldiers and Marines evaluated for discharge from service. This study describes the demographic, service-related, and disability characteristics of Soldiers and Marines referred for combat-related TBI disability evaluation. METHODS: Cross-sectional analysis of Soldiers and Marines evaluated for combat-related disability between October 1, 2004 and September 30, 2010 was performed. Traumatic brain injury cases were identified using the Veterans Affairs Schedule for Rating Disabilities code for TBI and compared with other combat-related disabilities. RESULTS: Combat-related TBI disability rates have significantly increased in both the Army and the Marine Corps since 2005. Significantly more unfitting conditions are present on average in combat-related TBI cases than in other combat-related disability cases. Combat-related TBI disability cases are more likely to be medically retired than other types of combat-related disability. CONCLUSIONS: Because veterans with combat-related TBI disabilities are likely to require chronic care for TBI-associated medical conditions, disability evaluation policy and programs must ensure that combat-related TBI disabilities are accurately identified and compensated, and the potential long-term care needs are addressed.

Association between antibodies to multiple infectious and food antigens and new onset schizophrenia among US military personnel.

INTRODUCTION: Multiple studies have documented immune activation in many individuals with schizophrenia suggesting that antigens capable of generating a prolonged immune response may be important environmental factors in many cases of this disorder. While existing studies have found single-agent associations of antibodies to food and neurotropic infectious agents with schizophrenia, a simultaneous examination of multiple agents may shed light on agent interactions or possible etiopathogenic pathways. METHODS: We used traditional regression and novel statistical techniques to examine associations of single and combined infectious and food antigens with schizophrenia. We tested 6106 serum samples from 855 cases and 1165 matched controls. RESULTS: Higher antibody levels to casein were borderline significant in the prediction of schizophrenia (HR=1.08, p=0.06). Study participants with higher cytomegalovirus (CMV) IgG antibody levels had a reduced risk of developing schizophrenia (HR=0.90; p=0.02). While IgG antibodies to gliadin, Toxoplasma gondii, vaccinia, measles, and human herpesvirus-6 (HHV-6) showed no significant independent associations with schizophrenia, the increase in antibody levels to several combinations of agents, to include casein, measles, CMV, T. gondii and vaccinia, was predictive of an 18-34% increase in the risk of developing schizophrenia. CONCLUSION: Certain patterns of antibodies, involving some agents, were predictive of developing schizophrenia, with the magnitude of association rising when the level of antibodies increased to two or more agents. A heightened antibody response to a combination of several infectious/food antigens might be an indicator of an altered immune response to antigenic stimuli.