David W. Niebuhr

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.

Development of a blood-based molecular biomarker test for identification of schizophrenia before disease onset.

Recent research efforts have progressively shifted towards preventative psychiatry and prognostic identification of individuals before disease onset. We describe the development of a serum biomarker test for the identification of individuals at risk of developing schizophrenia based on multiplex immunoassay profiling analysis of 957 serum samples. First, we conducted a meta-analysis of five independent cohorts of 127 first-onset drug-naive schizophrenia patients and 204 controls. Using least absolute shrinkage and selection operator regression, we identified an optimal panel of 26 biomarkers that best discriminated patients and controls. Next, we successfully validated this biomarker panel using two independent validation cohorts of 93 patients and 88 controls, which yielded an area under the curve (AUC) of 0.97 (0.95–1.00) for schizophrenia detection. Finally, we tested its predictive performance for identifying patients before onset of psychosis using two cohorts of 445 pre-onset or at-risk individuals. The predictive performance achieved by the panel was excellent for identifying USA military personnel (AUC: 0.90 (0.86–0.95)) and help-seeking prodromal individuals (AUC: 0.82 (0.71–0.93)) who developed schizophrenia up to 2 years after baseline sampling. The performance increased further using the latter cohort following the incorporation of CAARMS (Comprehensive Assessment of At-Risk Mental State) positive subscale symptom scores into the model (AUC: 0.90 (0.82–0.98)). The current findings may represent the first successful step towards a test that could address the clinical need for early intervention in psychiatry. Further developments of a combined molecular/symptom-based test will aid clinicians in the identification of vulnerable patients early in the disease process, allowing more effective therapeutic intervention before overt disease onset.

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

Abstract 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.

Exertional heat illness among overweight U.S. Army recruits in basic training.

INTRODUCTION Heat illness has not declined in the U.S. military despite preventive measures. The increase in overweight recruits entering the U.S. military may lead to an increase in heat-related events. This study compares the risk of heat illness among U.S. Army recruits who exceeded body fat standards at accession to those who met standards. METHODS Recruits with excess body fat and qualified applicants to the Army were required to take a preaccession fitness test during the study period (February 2005 through September 2006). The test included a 5-min step test and 1-min push-up challenge, scored as pass or fail. Incidence and outpatient usage for heat illness (any heat illness, heat stroke, heat exhaustion, and other heat illness) at 90 d of service were compared in 9667 male recruits of whom 826 had excess body fat and 8841 were qualified. There were too few heat events among women for analysis. RESULTS The incidence odds ratio among male recruits with excess body fat compared to qualified male recruits was 3.63 (95% CI: 1.92, 6.85). Men with excess body fat had an increased incidence of heat illness with a rate ratio of 7.25 (95% CI: 4.17, 12.61). DISCUSSION Although there were few heat illness events, the results indicate a significantly increased risk of heat illness and outpatient utilization among male recruits with excess body fat. It was estimated that approximately 70% of the relative risk for heat illnesses in men with excess body fat during basic training was associated with exceeding body fat standards. These findings may have implications for military accession and training.

Musculoskeletal injuries among overweight army trainees: incidence and health care utilization.

BACKGROUND Musculoskeletal injuries are a major cause of morbidity in military training. They are more common among overweight/obese individuals, and the prevalence of overweight/obesity in the military has increased. During strong economic periods, the military can be challenged to recruit enough qualified personnel, and physical standards are sometimes relaxed. AIMS This study was conducted to compare the incidence of and outpatient utilization for training-related overuse injuries among men who were over body fat (OBF) standards compared with those who were weight qualified (WQ). METHODS All study subjects were men ≥18 years old, who were classified as OBF or WQ and were followed for 90 days. During this period, everyone entering through the study sites was required to take a physical fitness test (5 min step test). Only individuals passing the fitness test were included in these analyses. RESULTS There were 812 OBF and 6511 WQ study participants. OBF were 47% more likely to experience a musculoskeletal injury and had 49% higher health care utilization. Other significant factors included age >19 and a history of smoking. CONCLUSIONS Among this population who had passed a fitness test, those who were OBF had a substantially higher risk of injury and higher utilization for these injuries. Because the recruiting environment is much better, military entrance standards have been tightened, but should the economy improve substantially the military may again be challenged to recruit adequate numbers of personnel, and the lessons learned in this project may prove valuable.

Assessment of recruit motivation and strength study: preaccession physical fitness assessment predicts early attrition.

BACKGROUND The Assessment of Recruit Motivation and Strength (ARMS) study was designed to pilot-test the use of a physical fitness screening tool for Army applicants before basic training. METHODS The ARMS test consists of two components, namely, a 5-minute step test and push-ups. Attrition among 7,612 recruits who underwent preaccession ARMS testing and began service between May 2004 and December 2005 was studied. RESULTS ARMS test performance was found to be significantly related to risk of attrition within 180 days; the hazard ratios for failing relative to passing the ARMS test were 2.27 (95% confidence interval, 1.70-3.04) among female subjects and 1.36 (95% confidence interval, 1.13-1.64) among male subjects. The attributable risk of attrition associated with failing the ARMS test was approximately 40% among female subjects and approximately 30% among male subjects. DISCUSSION The ARMS study is the first prospective study conducted in the U.S. Army to assess physical fitness before accession. Physical fitness and motivation to serve were shown to correlate with attrition during initial entry training.

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.

Step Test Performance and Risk of Stress Fractures Among Female Army Trainees

BACKGROUND Stress fractures and other musculoskeletal injuries are major sources of morbidity among female military trainees. Several risk factors have been postulated, particularly pre-existing fitness, usually assessed with post-entry run time for ≥ 1.0 mile. PURPOSE Physical fitness is not formally evaluated prior to Army entry. If a valid and simple test that identified women at increased risk of stress fracture were available and could be applied prior to entry, it would facilitate cost-benefit studies of deferral or interventions. These analyses were undertaken to determine if a 5-minute step test conducted before entry identified women at increased risk. METHODS A prospective study was conducted of weight-qualified women entering the Army in 2005-2006, with analyses completed in 2011. At the pre-entry examination, information was collected on age, BMI, smoking, race, and activity level. Everyone took the step test. All outpatient medical encounters were captured, and stress fractures and other musculoskeletal injuries identified. Women with stress fractures and those with other musculoskeletal injuries were evaluated separately. RESULTS 1568 women were included in the study; 109 developed stress fractures and 803 other musculoskeletal injury. Women who failed the step test had a 76% higher stress fracture incidence and a 35% higher incidence of other musculoskeletal injuries. There was effect modification between age and test failure for stress fracture. CONCLUSIONS A step test that can be administered before military entry identifies women with increased incidence of stress fracture and other musculoskeletal injury. This test could be used pre-entry to defer or target high-risk recruits for tailored fitness training before or after military entrance.

Physical training injuries and interventions for military recruits.

Low physical fitness levels are associated with increased musculoskeletal injury risk and attrition among military recruits. The authors review physical fitness trends, injury risk factors, and Department of the Army initiatives to address recruit fitness, injuries, and attrition. Initiatives include the Fitness Assessment Program, which reduced injury risk and attrition among low-fit trainees, and the Assessment of Recruit Motivation and Strength, which enabled the Army to enlist individuals exceeding body composition accession standards without increasing attrition. Physical Readiness Training (PRT) is the Armys primary initiative to address training-related injuries and attrition. PRTs inherent injury control and exercise progression components are designed to address low fitness levels across entry-level training. PRT has been shown to decrease injury rates, but low-fit recruits remain at increased risk regardless of program design. The authors recommend resuming pre-enlistment fitness screening and fitness programming before low-fit recruits begin entry-level training. The decision whether to screen for fitness before beginning entry-level training could be based upon the existing recruiting environment in terms of applicant supply and the demand for recruits. However, the Army should anticipate increased injury and attrition rates when discontinuing screening and/or fitness programming for low-fit recruits.

Preaccession Fitness and Body Composition as Predictors of Attrition in U.S. Army Recruits

The Assessment of Recruit Motivation and Strength (ARMS) project evaluated whether active duty Army enlistees who exceeded weight and body-fat standards but were able to pass the ARMS physical fitness test were at elevated risk of early attrition relative to the traditional recruit population. Attrition among 1146 overweight and overbody-fat (OBF) recruits who passed ARMS was compared to 10,514 fully qualified (FQ) recruits who began service in February 2005 through September 2006. The ARMS test includes a 5-minute step test and a 1-minute pushup test. There were no significant differences in attrition between OBF and FQ at 180 days: adjusted hazard ratios were 1.17 (95% CI: 0.83, 1.65) among females and 1.23 (95% CI: 0.95, 1.58) among males. This study indicates that physically fit recruits who exceeded weight/body-fat standards were equally capable of serving at least 180 days compared to those who met standards.