From autopoiesis to self-optimization: Toward an enactive model of biological regulation.

The theory of autopoiesis has been influential in many areas of theoretical biology, especially in the fields of artificial life and origins of life. However, it has not managed to productively connect with mainstream biology, partly for theoretical reasons, but arguably mainly because deriving specific working hypotheses has been challenging. The theory has recently undergone significant conceptual development in the enactive approach to life and mind. Hidden complexity in the original conception of autopoiesis has been explicated in the service of other operationalizable concepts related to self-individuation: precariousness, adaptivity, and agency. Here we advance these developments by highlighting the interplay of these concepts with considerations from thermodynamics: reversibility, irreversibility, and path-dependence. We interpret this interplay in terms of the self-optimization model, and present modeling results that illustrate how these minimal conditions enable a system to re-organize itself such that it tends toward coordinated constraint satisfaction at the system level. Although the model is still very abstract, these results point in a direction where the enactive approach could productively connect with cell biology.

Association of MOS-Based Blast Exposure With Medical Outcomes.

The study of effects associated with human exposure to repeated low-level blast during training or operations of select military occupational specialties (MOS) challenges medical science because acute negative effects that might follow such exposures cannot be expected to be clear or prevalent. Any gross effects from such occupational blast exposure on health or performance should be expected to have been already identified and addressed by affected military units through changes to their standard training protocols. Instead, effects, if any, should be expected to be incremental in nature and to vary among individuals of different susceptibilities and exposure histories. Despite the challenge, occupational blast-associated effects in humans are emerging in ongoing research. The purpose of the present study was to examine medical records for evidence of blast-associated effects that may have clinical significance in current standard of care. We hypothesized that populations exposed to blast by virtue of their military occupation would have poorer global medical outcomes than cohorts less likely to have been occupationally exposed. Records from a population of 50,254 service members in MOSs with a high likelihood of occupational blast exposure were compared to records from a matched cohort of 50,254 service members in MOSs with a lower likelihood of occupational blast exposure. These two groups were compared in hospitalizations, outpatient visits, pharmacy, and disability ratings. The clearest finding was higher risk among blast-exposed MOSs for ambulatory encounters for tinnitus, with adjusted risk ratios of 1.19 (CI 1.03-1.37), 1.21 (CI 1.16-1.26), and 1.31 (CI 1.18-1.45) across career time points. Other hypothesized effects (i.e., neurological outcomes) were smaller and were associated with acute exposure. This study documents that service members in occupations that likely include repeated exposure to blast are at some increased risk for neurosensory conditions that present in medical evaluations. Other hypothesized risks from occupational exposure may manifest as symptomology not visible in the medical system or current standard of care. Separate studies, observational and epidemiological, are underway to evaluate further the potential for occupational risk, but the evidence presented here may indicate near-term opportunities to guide efforts to reduce neurosensory risk among exposed service members.

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.

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.

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.

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.

Personality Assessment Questionnaire as a pre-accession screen for risk of mental disorders and early attrition in U. S. Army recruits.

Personality assessment tools have been studied as predictors of performance in civilian and military work settings. The Tailored Adaptive Personality Assessment System (TAPAS) was developed to improve selection of new military recruits by predicting motivational outcomes such as job effort, physical fitness, and drive to perform at high standards. The purpose of this study is to examine the utility of TAPAS as a predictor of psychiatric morbidity and early discharge in a sample of 15,082 Army, active duty, enlisted, nonprior service recruits. Associations between TAPAS personality dimension score quintiles and mental disorder diagnoses, attrition, and health care utilization in United States Army recruits who took TAPAS in the fiscal year 2010 were analyzed using multivariate logistic regression and log-linear modeling. TAPAS physical conditioning dimension scores were predictive of mental disorder diagnosis and attrition, with TAPAS scorers in the lowest quintile at increased odds of early discharge (odds ratio [OR]: 2.08, 95% CI 1.73, 2.51), mental disorder diagnosis (OR: 1.41, 95% CI 1.20, 1.66) and greater mental health care utilization (1.61, 95% CI 1.46, 1.78) compared with TAPAS scorers in the highest quintile. Results indicated that TAPAS may have an important use as a mental health fitness screening tool for those who wish to serve in the military by identifying a limited high risk group of applicants for mental health diagnostic evaluation. TAPAS may augment current cognitive and educational screens and potentially reduce the burden of mental disorders and premature attrition.

Descriptive epidemiology and underlying psychiatric disorders among hospitalizations with self-directed violence.

BACKGROUND: Suicide claims over one million lives worldwide each year. In the United States, 1 per 10,000 persons dies from suicide every year, and these rates have remained relatively constant over the last 20 years. There are nearly 25 suicide attempts for each suicide, and previous self-directed violence is a strong predictor of death from suicide. While many studies have focused on suicides, the epidemiology of non-fatal self-directed violence is not well-defined. OBJECTIVE: We used a nationally representative survey to examine demographics and underlying psychiatric disorders in United States (US) hospitalizations with non-fatal self-directed violence (SDV). METHOD: International Classification of Disease, 9(th) Revision (ICD-9) discharge diagnosis data from the National Hospital Discharge Survey (NHDS) were examined from 1997 to 2006 using frequency measures and adjusted logistic regression. RESULTS: The rate of discharges with SDV remained relatively stable over the study time period with 4.5 to 5.7 hospitalizations per 10,000 persons per year. Excess SDV was documented for females, adolescents, whites, and those from the Midwest or West. While females had a higher likelihood of self-poisoning, both genders had comparable proportions of hospitalizations with SDV resulting in injury. Over 86% of the records listing SDV also included psychiatric disorders, with the most frequent being affective (57.8%) and substance abuse (37.1%) disorders. The association between psychiatric disorders and self-injury was strongest for personality disorders for both males (OR = 2.1; 95% CI = 1.3-3.4) and females (OR = 3.8; 95% CI = 2.7-5.3). CONCLUSION: The NHDS provides new insights into the demographics and psychiatric morbidity of those hospitalized with SDV. Classification of SDV as self-injury or self-poisoning provides an additional parameter useful to epidemiologic studies.

A noncognitive temperament test to predict risk of mental disorders and attrition in U.S. Army recruits.

UNLABELLED: U.S. military accession mental health screening includes cognitive testing and questions regarding the applicants' past mental health history. This process relies on applicants' knowledge of and willingness to disclose symptoms and conditions. Applicants have a strong incentive to appear qualified, which has resulted in a long history of frequent mental health conditions presenting during recruit training. OBJECTIVE: To assess the predictive value of a pre-enlistment noncognitive temperament test score for risk of mental disorders and attrition in the first year of service. METHODS: A retrospective cohort study was conducted on non-high school diploma U.S. Army active duty recruits who took the Assessment of Individual Motivation (AIM). Multivariate logistic regression models were used to determine associations between AIM score quintiles, mental disorders, and attrition. RESULTS: AIM scorers in the lowest quintile were at increased risk for a mental disorder (OR, 1.44; 95% CI, 1.35-1.53) and of discharge (OR, 1.65; 95% CI, 1.44-1.68) compared to AIM scorers in the highest quintile, with significant linear trends for decreased risk with increasing AIM score. CONCLUSIONS: AIM offers the potential to improve screening of military applicants and reduce mental disorders and attrition in new recruits beyond the current process.

National estimates of seroincidence and seroprevalence for herpes simplex virus type 1 and type 2 among US military adults aged 18 to 29 years.

BACKGROUND: While population-based seroprevalence studies of herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) are widespread, seroincidence studies are largely limited to select or high-risk populations. The US military offers a potential population to derive national seroincidence rate estimates for young adults (ages 18-29). METHODS: We used banked, longitudinal serum specimens collected in a cohort of 1094 military personnel aged 18 to 30 years who served between 1989 and 2005 to estimate national HSV-1 and HSV-2 seroincidence and seroprevalence for the young, adult military population, weighted according to the US Census. Serum was tested with indirect ELISA (enzyme-linked immunosorbent assay). RESULTS: Estimated national seroincidence rates for the US young, adult military population were 9.1 per 100 person-years (95% confidence interval: 4.6-13.5) for HSV-1 and 6.2 (95% confidence interval: 3.1-9.3) for HSV-2. Female sex and black race were associated with significantly higher HSV-2 seroconversion rates. Our estimated HSV1/2 seroprevalences were comparable to US national data provided by National Health and Nutrition Examination Surveys' serosurveys except for non-Hispanic blacks and Hispanics. CONCLUSION: Although these US 2000 Census-weighted estimates of HSV-1 and HSV-2 seroincidence apply only to young, military adults, they nonetheless supply, to our knowledge, the only national figures that might be used to predict US national HSV1/2 seroincidence in young adults. Thus, we believe that our findings in this military population can be used to inform the planning of HSV-1 and 2 prevention measures in the general, young-adult US population.

Identification of a blood-based biological signature in subjects with psychiatric disorders prior to clinical manifestation.

OBJECTIVES: To determine whether a molecular signature is present in blood of patients with psychiatric disorders before manifestation of symptoms. METHODS: Multiplex immunoassay analyses were carried out using serum obtained from two case-control studies of schizophrenia (n = 75) and bipolar disorder (n = 110) patients and their matched controls. The samples were drawn within 1 month before estimated onset of illness. RESULTS: This led to identification of 20 molecules which were altered in pre-schizophrenia and 14 molecules in pre-bipolar disorder subjects compared to controls. Only two of these molecular changes were identical in both data sets and predictive testing confirmed that the biomarker signatures for pre-schizophrenia and pre-bipolar disorder were dissimilar. CONCLUSION: The present results suggest that there are distinct serum alterations that occur before clinical manifestation of schizophrenia and bipolar disorder. These findings could lead to development of diagnostic tests to help clinical psychiatrists identify and classify vulnerable patients early in the disease process, allowing for earlier and more effective therapeutic intervention.

Psychiatric and general medical conditions comorbid with bipolar disorder in the National Hospital Discharge Survey.

OBJECTIVE: From 40% to 65% of patients with bipolar disorder are estimated to have diagnoses of one or more comorbid conditions. The purpose of this study was to identify comorbid disorders and compare their prevalence in hospitalizations of persons with or without bipolar disorder. METHODS: Data from the 1979-2006 National Hospital Discharge Survey (NHDS) were analyzed to examine temporal trends in the proportional morbidity of bipolar disorder, demographic characteristics, and the most frequent comorbid conditions in hospitalizations of patients with or without bipolar disorder. Among discharges of patients ages 13-64, the conditions of those with a primary diagnosis of bipolar disorder (N=27,054) were compared with those with other primary diagnoses (N=2,325,247). Proportional morbidity ratios (PMRs) were calculated. RESULTS: There was an average 10% (p<.001) increase per year in the proportion of discharges with bipolar disorder. Proportions of discharge records that noted bipolar disorder were higher among females and whites and were highest among persons ages 13-19 and those from the Northeast. Discharge records noting a primary diagnosis of bipolar disorder showed higher proportions of most psychiatric and some general medical conditions, including acquired hypothyroidism (proportional morbidity ratio=2.6), viral hepatitis (1.6), obesity (1.4), and various diseases of the skin and subcutaneous tissue (range 2.6-4.2) and of the nervous (1.4-3.8), respiratory (1.4-2.3), and musculoskeletal (1.2-1.9) systems. CONCLUSIONS: Patients with bipolar disorder have an increased illness burden from many psychiatric and general medical conditions. Knowledge of the most prevalent comorbid conditions and methods for their prevention, early diagnosis, and treatment are critical in improving the prognosis of patients with bipolar disorder.

Association between bovine casein antibody and new onset schizophrenia among US military personnel.

Schizophrenia is a pervasive neuropsychiatric disorder of uncertain etiology. Multiple studies have documented immune activation in individuals with schizophrenia. One antigen capable of inducing a prolonged immune response is bovine casein derived from ingested milk products. Increased levels of casein antibodies have been found in individuals with schizophrenia after diagnosis. This study was directed at determining the potential association between schizophrenia and pre-illness onset levels of immunoglobulin G (IgG) antibodies to bovine casein. Parallel analyses for casein antibody levels with bipolar disorder were included as comparison. Cases were service members who received medical discharges from the military with a schizophrenia diagnosis from 1992 to 2005. Serum specimens were selected for 855 cases and 1165 matched healthy controls. IgG antibodies to bovine whole-casein were measured by solid phase enzyme-linked immunosorbent assays (ELISAs). Hazard ratios (HR) were calculated to examine the associations of casein IgG level with risk of schizophrenia by time to diagnosis and by subjects' initial level. Increasing casein IgG antibody levels among those with a high initial level, drawn before diagnosis, was associated with an 18% increase in the hazard risk of schizophrenia per unit increase (value of low-positive standard) in IgG antibody levels (HR=1.18; 95% CI 1.04, 1.34). This is the first report to identify an association between the risk of schizophrenia and elevated antibodies to bovine casein prior to disease onset. Additional research is required to elucidate the complex genetic environmental interactions involved in the pathogenesis of schizophrenia and to identify potentially modifiable risk factors.

Incidence of adult onset schizophrenic disorders in the US military: patterns by sex, race and age.

BACKGROUND: There are limited data describing the epidemiology of adult-onset schizophrenic disorders in the United States. Although the military is not proportionately comparable in all demographic characteristics to the civilian population, it is drawn from all racial/ethnic subgroups, and members range in age from 17 to >60 years. We describe the incidence of hospitalization for new onset schizophrenic disorders among military members by sex, race, and age. METHODS: Using military inpatient data, we evaluated patterns of initial hospitalizations for schizophrenic disorders among military personnel for 2000-2009, focusing on sex, race, and age. No individual-level data were available. RESULTS: From 2000-2009, 1976 military personnel had a first schizophrenic disorder hospitalization, with an overall incidence rate of 0.14/1000 person-years. There were no consistent changes in rates over time. While overall incidence rates were similar for men and women (incidence rate ratio (IRR)=1.10), rates were higher among men than women below age 25; after 25-30 rates were higher among women. Incidence was higher among blacks and other racial groups, with IRR=2.0 and 1.3, respectively. CONCLUSION: Medical screening of military applicants prevents persons with overt or a reported history of psychosis, and most with serious behavior problems, from enlisting; therefore, first hospitalization is likely to reflect new illness. No pre-military socioeconomic data were available, however, essentially all study subjects were high school graduates; unmeasured differences in socioeconomic status were unlikely to explain the observed results. This report may provide lower bound estimates of the schizophrenic disorder incidence in the United States.

Validation of a blood-based laboratory test to aid in the confirmation of a diagnosis of schizophrenia.

We describe the validation of a serum-based test developed by Rules-Based Medicine which can be used to help confirm the diagnosis of schizophrenia. In preliminary studies using multiplex immunoassay profiling technology, we identified a disease signature comprised of 51 analytes which could distinguish schizophrenia (n = 250) from control (n = 230) subjects. In the next stage, these analytes were developed as a refined 51-plex immunoassay panel for validation using a large independent cohort of schizophrenia (n = 577) and control (n = 229) subjects. The resulting test yielded an overall sensitivity of 83% and specificity of 83% with a receiver operating characteristic area under the curve (ROC-AUC) of 89%. These 51 immunoassays and the associated decision rule delivered a sensitive and specific prediction for the presence of schizophrenia in patients compared to matched healthy controls.

Descriptive epidemiology of bipolar I disorder among United States military personnel.

Psychiatric disorders in military members require substantial medical, administrative, and financial resources, and are among the leading causes of hospitalization and early discharge. We reviewed available data to better understand the incidence of bipolar I disorder among military personnel. Defense Medical Epidemiology Database inpatient data were used. Descriptive and comparative statistics were performed. From 1997-2006 there were 3,317 first hospitalizations for bipolar I disorder with a mean of 1.2 hospitalizations per case. The rate of first occurrence among this adult population was 0.24 per 1,000 person-years. The incidence increased over time for depressed and mixed episode types among both genders. High risk groups include women, younger individuals, and whites. This population provides insight into adult onset bipolar I disorder incidence and demographic patterns not available elsewhere and offers potential opportunities to improve its understanding.

Psychiatric and general medical conditions comorbid with schizophrenia in the National Hospital Discharge Survey.

OBJECTIVE: Morbidity and mortality from general medical conditions are elevated among patients with schizophrenia compared with the general U.S. population. More than 50% of patients with schizophrenia have one or more comorbid psychiatric or general medical conditions. This study determined types of comorbid disorders and their prevalence among hospitalized patients with and without schizophrenia. METHODS: Data from the National Hospital Discharge Survey, a nationally representative sample, were analyzed for 1979-2003 (N=5,733,781 discharges). For discharges of patients aged 15 to 64 with at least one comorbid condition, the conditions of those with a primary diagnosis of schizophrenia (N=26,279) were compared with those with other primary diagnoses (N=1,936,876). Proportional morbidity ratios (PMRs) were calculated. RESULTS: The proportion of discharges listing schizophrenia, particularly schizoaffective disorder, increased significantly over time among both males and females. The proportion was higher among males, blacks, and discharges in the Northeast. Discharge records with a primary diagnosis of schizophrenia showed higher proportions of all comorbid psychiatric conditions examined and of some general medical conditions, including acquired hypothyroidism (PMR=2.9), contact dermatitis and other eczema (PMR=2.9), obesity (PMR=2.0), epilepsy (PMR=2.0), viral hepatitis (PMR=1.4), diabetes type II (PMR=1.2), essential hypertension (PMR=1.2), and various chronic obstructive pulmonary diseases (PMR range 1.2-1.5). CONCLUSIONS: Knowledge of the risks of comorbid psychiatric and general medical conditions is critical both for clinicians and for patients with schizophrenia. Closer attention to prevention, early diagnosis, and treatment of comorbid conditions may decrease associated morbidity and mortality and improve prognosis among patients with schizophrenia.

Selected infectious agents and risk of schizophrenia among U.S. military personnel.

OBJECTIVE: A number of studies have reported associations between Toxoplasma gondii (T. gondii) infection and the risk of schizophrenia. Most existing studies have used small populations and postdiagnosis specimens. As part of a larger research program, the authors conducted a hypothesis-generating case control study of T. gondii antibodies among individuals discharged from the U.S. military with a diagnosis of schizophrenia and serum specimens available from both before and after diagnosis. METHOD: The patients (N=180) were military members who had been hospitalized and discharged from military service with a diagnosis of schizophrenia. Healthy comparison subjects (3:1 matched on several factors) were members of the military who were not discharged. The U.S. military routinely collects and stores serum specimens of military service members. The authors used microplate-enzyme immunoassay to measure immunoglobulin G (IgG) antibody levels to T. gondii, six herpes viruses, and influenza A and B viruses and immunoglobulin M (IgM) antibody levels to T. gondii in pre- and postdiagnosis serum specimens. RESULTS: A significant positive association between the T. gondii IgG antibody and schizophrenia was found; the overall hazard ratio was 1.24. The association between IgG and schizophrenia varied by the time between the serum specimen collection and onset of illness. CONCLUSION: The authors found significant associations between increased levels of scaled T. gondii IgG antibodies and schizophrenia for antibodies measured both prior to and after diagnosis.

Results from a hypothesis generating case-control study: herpes family viruses and schizophrenia among military personnel.

BACKGROUND: Herpes family viruses can cause central nervous system inflammatory changes that can present with symptoms indistinguishable from schizophrenia and therefore are of interest in schizophrenia research. Most existing studies of herpes viruses have used small populations and postdiagnosis specimens. As part of a larger research program, we conducted a hypothesis-generating case-control study of selected herpes virus antibodies among individuals discharged from the US military with schizophrenia and pre- and postdiagnosis sera. METHODS: Cases (n = 180) were servicemembers hospitalized and discharged from military service with schizophrenia. Controls, 3:1 matched on several factors, were members not discharged. The military routinely collects and stores members' serum specimens. We used microplate enzyme immunoassay to measure immunoglobulin G (IgG) antibody levels to 6 herpes viruses in pre- and postdiagnosis specimens. Conditional logistic regression was used, and the measure of association was the hazard ratio (HR). RESULTS: Overall, we found a significant association between human herpes virus type 6 and schizophrenia, with an HR of 1.17 (95% confidence interval [CI] = 1.04, 1.32). Women and blacks had significant negative associations with herpes simplex virus type 2 and cytomegalovirus; among blacks, there was a significant positive association with herpes simplex virus type 1. Among men, there was a HHV-6 temporal effect with an HR of 1.41 (95% CI = 1.02, 1.96) for sera drawn 6-12 months before diagnosis. DISCUSSION: Findings from previous studies of herpes family viruses and schizophrenia have been inconsistent. Our study is based on a larger population than most previous studies and used serum specimens collected before onset of illness. This study adds to the body of knowledge and provides testable hypotheses for follow-on studies.

Evaluation of data obtained from military disability medical administrative databases for service members with schizophrenia or bipolar disorder.

OBJECTIVE: We are studying associations between selected biomarkers and schizophrenia or bipolar disorder among military personnel. To assess potential diagnostic misclassification and to estimate the date of illness onset, we reviewed medical records for a subset of cases. METHODS: Two psychiatrists independently reviewed 182 service medical records retrieved from the Department of Veterans Affairs. Data were evaluated for diagnostic concordance between database diagnoses and reviewers. Interreviewer variability was measured by using proportion of agreement and the kappa statistic. Data were abstracted to estimate date of onset. RESULTS: High levels of agreement existed between database diagnoses and reviewers (proportion, 94.7%; kappa = 0.88) and between reviewers (proportion, 92.3%; kappa = 0.87). The median time between illness onset and initiation of medical discharge was 1.6 and 1.1 years for schizophrenia and bipolar disorder, respectively. CONCLUSIONS: High levels of agreement between investigators and database diagnoses indicate that diagnostic misclassification is unlikely. Discharge procedure initiation date provides a suitable surrogate for disease onset.