Inheritance model introduces differential bias in CNV calls between parents and offspring.

Copy Number Variation (CNV) is increasingly implicated in disease pathogenesis. CNVs are often identified by statistical models applied to data from single nucleotide polymorphism panels. Family information for samples provides additional information for CNV inference. Two modes of PennCNV (the Joint-call and Posterior-call), which are some of the most well-developed family-based CNV calling methods, use a "Joint-model" as a main component. This models all family members' CNV states together with Mendelian inheritance. Methods based on the Joint-model are used to infer CNV calls of cases and controls in a pedigree, which may be compared to each other to test an association. Although benefits from the Joint-model have been shown elsewhere, equality of call rates in parents and offspring has not been evaluated previously. This can affect downstream analyses in studies that compare CNV rates in cases vs. controls in pedigrees. In this paper, we show that the Joint-model can introduce different CNV call rates among family members in the absence of a true difference. We show that the Joint-model may analytically introduce differential CNV calls because of asymmetry of the model. We demonstrate these differential call rates using single-marker simulations. We show that call rates using the two modes of PennCNV also differ between parents and offspring in one multimarker simulated dataset and two real datasets. Our results advise need for caution in use of the Joint-model calls in CNV association studies with family-based datasets.

Verbal working memory impairments in individuals with schizophrenia and their first-degree relatives: findings from the Consortium on the Genetics of Schizophrenia.

Working memory (WM) impairment is a promising candidate endophenotype for schizophrenia that could facilitate the identification of susceptibility genes for this disorder. The validity of this putative endophenotype was assessed by determining whether 149 probands with schizophrenia and 337 of their first-degree relatives demonstrated WM impairment as compared to 190 unaffected community comparison subjects. Subjects were participants in the Consortium on the Genetics of Schizophrenia (COGS) project, a seven-site research network that was established to investigate the genetic architecture of endophenotypes for schizophrenia. Participants received comprehensive clinical assessments and completed two verbal WM tasks, one requiring transient on-line storage and another requiring maintenance plus complex manipulation of information by reordering the stimuli. Schizophrenia probands performed worse than the other groups on both tasks, with larger deficits found for the more challenging reordering WM task. The probands' relatives performed more poorly than community comparison subjects on both tasks, but the difference was significant only for the more challenging maintenance plus complex manipulation WM task. This WM impairment was not attributable to diagnoses of schizophrenia spectrum disorder, mood disorders, or substance use disorders in the relatives. In conjunction with evidence that WM abilities are substantially heritable, the current results support the validity and usefulness of verbal WM impairments in manipulation of information as endophenotypes for schizophrenia in large-scale genetic linkage and association studies.

Characteristics of deployed Operation Iraqi Freedom military personnel who seek mental health care.

INTRODUCTION: This study reports on the feasibility of using validated mental health screening instruments for deployed Operation Iraqi Freedom military personnel. METHODS: For a 3-month period in 2005, all service members (N=296) who initially presented to the U.S. Military Hospital Kuwait mental health clinic completed an intake questionnaire that gathered demographic information and contained validated instruments to screen for mental disorders and functional impairment. RESULTS: A total of 19% of the sample subjects screened positive for post-traumatic stress disorder-related symptoms, 35% for a major depressive disorder, and 11% for severe misuse of alcohol. Significant levels of distress and functional impairment were reported by 58% of the sample. Women represented a disproportionately high percentage of those presenting for care (27%). CONCLUSIONS: Screening instruments were well accepted and useful in detecting psychopathological conditions and functional impairment. Female service members might represent a high-risk group. These results are useful for those caring for service members during or after deployment.

Successful multi-site measurement of antisaccade performance deficits in schizophrenia.

The antisaccade task is a promising schizophrenia endophenotype; it is stable over time and reflects neurophysiological deficits present in both schizophrenia subjects and their first-degree relatives. Meaningful genetic research requires large sample sizes that are best ascertained using multi-site study designs. To establish the criterion validity of the antisaccade task in a multi-site design, the Consortium on the Genetics of Schizophrenia (COGS) examined whether seven sites could detect previously reported antisaccade deficits in schizophrenia subjects. Investigators presented 3 blocks of 20 antisaccade stimuli to 143 schizophrenia subjects and 195 comparison subjects. Frequent collaborator communication, standardized training, and ongoing quality assurance optimized testing uniformity. Data were discarded from only 1.2% of subjects due to poor quality, reflecting the high fidelity of data collection and scoring methods. All sites detected a significant difference in the proportion of correct antisaccades between schizophrenia and comparison subjects (p<.02 at all sites); group differences in gain and latency were less robust. Regression analyses to adjust for the effects of group, site, age, gender, smoking, and parental education on the proportion of correct antisaccades revealed a significant effect of group, site, and age but no effect of gender, smoking, or parental education, and no group-by-site interactions. Intraclass correlations between proportion of correct antisaccades across the blocks of stimuli ranged from 0.87 to 0.93, demonstrating good within-session reliability at sites. These results confirm previous findings of antisaccade deficits in schizophrenia subjects and support the use of the antisaccade task as a potential schizophrenia endophenotype in multi-site genetic studies.

Multi-site studies of acoustic startle and prepulse inhibition in humans: initial experience and methodological considerations based on studies by the Consortium on the Genetics of Schizophrenia.

BACKGROUND: Startle and its inhibition by weak lead stimuli ("prepulse inhibition": PPI) are studied to understand the neurobiology of information processing in patients and community comparison subjects (CCS). PPI has a strong genetic basis in infrahumans, and there is evidence for its heritability, stability and reliability in humans. PPI has gained increasing use as an endophenotype to identify vulnerability genes for brain disorders, including schizophrenia. Genetic studies now often employ multiple, geographically dispersed test sites to accommodate the need for large and complex study samples. Here, we assessed the feasibility of using PPI in multi-site studies. METHODS: Within a 7-site investigation with multiple measures, the Consortium on the Genetics of Schizophrenia conducted a methodological study of acoustic startle and PPI in CCS. Methods were manualized, videotaped and standardized across sites with intensive in-person training sessions. Equipment was acquired and programmed at the "PPI site" (UCSD), and stringent quality assurance (QA) procedures were used. Testing was completed on 196 CCS over 2.5 years, with 5 primary startle dependent measures: eyeblink startle magnitude, habituation, peak latency, latency facilitation and PPI. RESULTS: Analyses identified significant variability across sites in some but not all primary measures, and determined factors both within the testing process and subject characteristics that influenced a number of test measures. QA procedures also identified non-standardized practices with respect to testing methods and procedural "drift", which may be particularly relevant to multi-site studies using these measures. CONCLUSION: With thorough oversight and QA procedures, measures of acoustic startle PPI can be acquired reliably across multiple testing sites. Nonetheless, even among sites with substantial expertise in utilizing psychophysiological measures, multi-site studies using startle and PPI as dependent measures require careful attention to methodological procedures.

The Consortium on the Genetics of Endophenotypes in Schizophrenia: model recruitment, assessment, and endophenotyping methods for a multisite collaboration.

BACKGROUND: The Consortium on the Genetics of Schizophrenia (COGS) is an ongoing, National Institute of Mental Health-funded, 7-site collaboration investigating the occurrence and genetic architecture of quantitative endophenotypes related to schizophrenia. The purpose of this article is to provide a description of the COGS structure and methods, including participant recruitment and assessment. METHODS: The hypothesis-driven recruitment strategy ascertains families that include a proband with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnosis of schizophrenia, and at least one unaffected full sibling available for genotyping and endophenotyping, along with parents available for genotyping and (optional depending on age) endophenotyping. The family structure is selected to provide contrast in quantitative endophenotypic traits and thus to maximize the power of the planned genetic analyses. Probands are recruited from many sources including clinician referrals, local National Alliance for the Mentally Ill chapters, and advertising via the media. All participants undergo a standardized protocol that includes clinical characterization, a blood draw for genotyping, and endophenotype assessments (P50 suppression, prepulse inhibition, antisaccade performance, continuous performance tasks, letter-number span, verbal memory, and a computerized neurocognitive battery). Investigators participate in weekly teleconferences to coordinate and evaluate recruitment, clinical assessment, endophenotyping, and continuous quality control of data gathering and analyses. Data integrity is maintained through use of a highly quality-assured, centralized web-based database. RESULTS: As of February 2006, 355 families have been enrolled and 688 participants have been endophenotyped, including schizophrenia probands (n = 154, M:F = 110:44), first-degree biological relatives (n = 343, M:F = 151:192), and community comparison subjects (n = 191, M:F = 81:110). DISCUSSION: Successful multisite genetics collaborations must institute standardized methodological criteria for assessment and recruitment that are clearly defined, well communicated, and uniformly applied. In parallel, studies utilizing endophenotypes require strict adherence to criteria for cross-site data acquisition, equipment calibration and testing and software equivalence, and continuous quality assurance for many measures obtained across sites. This report describes methods and presents the structure of the COGS as a model of multisite endophenotype genetic studies. It also provides demographic information after the first 2 years of data collection on a sample for whom the behavioral data and genetics of endophenotype performance will be fully characterized in future articles. Some issues discussed in the reviews that follow reflect the challenges of evaluating endophenotypes in studies of the genetic architecture of endophenotypes in schizophrenia.

Frequency of mastalgia among women veterans. Association with psychiatric conditions and unexplained pain syndromes.

OBJECTIVE: To determine the prevalence and frequency of mastalgia and its association with psychiatric conditions and unexplained pain syndromes. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional mailed survey completed by 1,219 female veterans enrolled at the VA Puget Sound Health Care System in 1998. MEASUREMENTS: Breast pain in the past year, unrelated to pregnancy, was categorized as infrequent (< or =monthly) or frequent (> or =weekly) mastalgia. Surveys assessed posttraumatic stress disorder (PTSD), depression, panic disorder, and alcohol misuse with validated screening tests, as well as self-reported past-year chronic pelvic pain, fibromyalgia, and irritable bowel syndrome. RESULTS: The response rate was 63%. Fifty-five percent of the respondents reported past-year mastalgia. Of these, 15% reported frequent mastalgia. Compared to women without mastalgia, women reporting frequent mastalgia were more likely to screen positive for PTSD (odds ratio [OR] 5.2, 95% confidence interval [CI] 3.2 to 8.4), major depression (OR 4.2, 2.6 to 6.9), panic disorder (OR 7.1, 3.9 to 12.8), eating disorder (OR 2.6, 1.5 to 4.7), alcohol misuse (OR 1.8, 1.1 to 2.8), or domestic violence (OR 3.1, 1.9 to 5.0), and to report fibromyalgia (OR 3.9, 2.1 to 7.4), chronic pelvic pain (OR 5.4, 2.7 to 10.5), or irritable bowel syndrome (OR 2.8, 1.6 to 4.8). Women with infrequent mastalgia were also more likely than women without mastalgia to screen positive for PTSD, depression, or panic disorder, or report pelvic pain or irritable bowel syndrome, although associations were weaker than with frequent mastalgia. CONCLUSIONS: Like other unexplained pain syndromes, frequent mastalgia is strongly associated with PTSD and other psychiatric conditions. Clinicians seeing patients with frequent mastalgia should inquire about anxiety, depression, alcohol misuse, and trauma history.

Posttraumatic stress disorder screening status is associated with increased VA medical and surgical utilization in women.

BACKGROUND: Women with posttraumatic stress disorder (PTSD) report poor health, but associations with health care utilization are understudied. OBJECTIVE: To determine associations between medical/surgical utilization and PTSD in female Veterans Affairs (VA) patients. DESIGN: Prospective comparison of utilization rates between women screening positive or negative for PTSD on a mailed survey. SUBJECTS: Women receiving care at an urban VA medical center between October 1996 and January 2000. MEASUREMENTS: Survey responses, including a validated screen for PTSD (PCL-C), and VA utilization data through September 2002. RESULTS: Two thousand five hundred and seventy-eight (2,578) women (78% of those eligible) completed the PCL-C; 858 (33%) of them screened positive for PTSD (PTSD+). In unadjusted models, PTSD+ women had higher rates of medical/surgical hospitalizations and surgical inpatient procedures. Among women ages 35 to 49, mean days hospitalized/100 patients/year was 43.4 (95% CI 26 to 61) for PTSD+ women versus 17.0 (16 to 18) for PTSD negative (PTSD-) women. More PTSD+ women underwent surgical procedures (P<.001). Mean annual outpatient visits were significantly higher among PTSD+ women, including: emergency department (ED) (1.1 [1.0 to 1.2] vs 0.6 [0.5 to 0.6]), primary care (3.2 [3.0 to 3.4] vs 2.2 [2.1 to 2.3]), medical/surgical subspecialists (2.1 [1.9 to 2.3] vs 1.5 [1.4 to 1.6]), ancillary services (4.1 [3.7 to 4.5] vs 2.4 [2.2 to 2.6]), and diagnostic tests (5.6 [5.1 to 6.1] vs 3.7 [3.4 to 4.0]). In multivariate models adjusted for demographics, smoking, service access, and medical comorbidities, PTSD+ women had greater likelihood of medical/surgical hospitalization (OR=1.37 [1.04 to 1.79]) and of being among the top quartile of patients for visits to the ED, primary care, ancillary services, and diagnostic testing. CONCLUSIONS: Female veterans who screen PTSD+ receive more VA medical/surgical services. Appropriateness of that care deserves further study.

A brief readiness to change drinking algorithm: concurrent validity in female VA primary care patients.

Brief primary care interventions for alcohol use should be tailored to patients' readiness to change; however, validated measures of readiness to change are too lengthy to be practical in most primary care settings. We compared a readiness to change drinking algorithm (RTC Algorithm) based on three standardized questions to a validated 12-item readiness to change questionnaire (Rollnick RTCQ) in 85 hazardous drinking female Veterans Affairs (VA) patients. Results from comparisons of mean Rollnick RTCQ scale scores across RTC Algorithm categories suggest good concurrent validity. Regular assessment using the RTC Algorithm questions may help primary care providers tailor alcohol-related discussions with hazardous drinking patients.

Posttraumatic stress disorder in female veterans: association with self-reported health problems and functional impairment.

BACKGROUND: The purpose of this report is to identify self-reported health problems and functional impairment associated with screening positive for posttraumatic stress disorder (PTSD) in women seen for care at a Department of Veterans Affairs (VA) medical center. METHODS: A survey was mailed to all women (N = 1935) who received care at the VA Puget Sound Health Care System between October 1996 and January 1998. The survey inquired about health history and habits. It included the PTSD Checklist-Civilian Version (PCL-C) and validated screening measures for other psychiatric disorders. The veteran's version of the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36-V) was included to assess health-related quality of life. RESULTS: Of the 1259 eligible women who completed the survey, 266 women (21%) screened positive for current PTSD (PCL-C score >or= 50). In age-adjusted bivariate analyses, women who screened positive for PTSD reported more psychiatric problems, substance abuse, and lifetime exposure to domestic violence. They were significantly more likely to endorse physical health problems including obesity, smoking, irritable bowel syndrome, fibromyalgia, chronic pelvic pain, polycystic ovary disease, asthma, cervical cancer, and stroke. In fully adjusted multivariate models, a PCL-C score of 50 or greater was independently associated with scoring in the lowest quartile on SF-36-V subscales and composite scales. CONCLUSIONS: Symptoms of PTSD are common in women treated at VA facilities. In addition, PTSD is associated with self-reported mental and physical health problems and poor health-related quality of life in these patients. These findings have implications for the design of VA primary care services for the growing population of female veterans.

Two brief alcohol-screening tests From the Alcohol Use Disorders Identification Test (AUDIT): validation in a female Veterans Affairs patient population.

BACKGROUND: Primary care physicians need a brief alcohol questionnaire that identifies hazardous drinking and alcohol use disorders. The Alcohol Use Disorders Identification Test (AUDIT) questions 1 through 3 (AUDIT-C), and AUDIT question 3 alone are effective alcohol-screening tests in male Veterans Affairs (VA) patients, but have not been validated in women. METHODS: Female VA patients (n = 393) completed self-administered questionnaires, including the 10-item AUDIT and a previously proposed modification to AUDIT question 3 with a sex-specific threshold for binge drinking (>/=4 drinks/occasion), and in-person interviews with the Alcohol Use Disorder and Associated Disabilities Interview Schedule. The AUDIT-C, AUDIT question 3 alone, and the 10-item AUDIT were each evaluated with and without the sex-specific binge question and compared with past-year hazardous drinking (>7 drinks/week or >/=4 drinks/occasion) and/or active Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition alcohol abuse or dependence, based on interviews. RESULTS: Eighty-nine women (22.6%) met interview criteria for past-year hazardous drinking and/or active alcohol abuse or dependence. Standard and sex-specific AUDIT-Cs were sensitive (0.81 and 0.84, respectively) and specific (0.86 and 0.85, respectively). Their areas under the receiver operating characteristic curves were equivalent (0.91, and 0.92, respectively) and slightly higher than for the standard 10-item AUDIT (0.87). A single, sex-specific question about binge drinking (modified AUDIT question 3) had a sensitivity of 0.69 and specificity of 0.94, whereas the standard AUDIT question 3 was specific (0.96) but relatively insensitive (0.45). CONCLUSIONS: The standard and sex-specific AUDIT-Cs are effective screening tests for past-year hazardous drinking and/or active alcohol abuse or dependence in female patients in a VA study.

Prevalence of hysterectomy and associated factors in women Veterans Affairs patients.

OBJECTIVE: To estimate the prevalence of hysterectomy and associated factors in women veterans who access care at a Veterans Affairs medical center. STUDY DESIGN: A survey that included questions regarding hysterectomy status, demographics, medical history and validated mental health measures was mailed to 1,935 women who received care at the VA Puget Sound Health Care System between October 1996 and January 1998. RESULTS: The overall prevalence of hysterectomy was 32%, with 12% of 18-39-year-olds, 35% of 40-49-year-olds, and 57% of women 50 years old or older reporting having had a hysterectomy. In multivariable analyses, older age (OR 1.1, 95% CI 1.07-1.09), multiparity (OR 1.6, 1.14-2.2), self-reported polycystic ovary syndrome (OR 3.3, 1.81-5.9), chronic pelvic pain (OR 3.2, 2.1-4.9), irritable bowel syndrome (OR 1.8, 1.3-3.1) and premenstrual syndrome (OR 1.6, 1.1-2.3) were associated with prior hysterectomy. When factors associated with posttraumatic stress disorder in this population were omitted from the model, age (OR 1.07, 1.05-1.08), multiparity (OR 1.4, 1.0-1.9), a family history of ovarian cancer (OR 1.8, 1.2-2.8) and posttraumatic stress disorder (OR 1.4, 1.02-1.87) were associated with prior hysterectomy. CONCLUSION: The prevalence of hysterectomy may be higher among women veterans as compared with published rates for the general population and may be related to chronic pain syndromes and/or posttraumatic stress disorder.

Neurocognitive performance in family-based and case-control studies of schizophrenia.

BACKGROUND: Neurocognitive deficits in schizophrenia (SZ) are established and the Consortium on the Genetics of Schizophrenia (COGS) investigated such measures as endophenotypes in family-based (COGS-1) and case-control (COGS-2) studies. By requiring family participation, family-based sampling may result in samples that vary demographically and perform better on neurocognitive measures. METHODS: The Penn computerized neurocognitive battery (CNB) evaluates accuracy and speed of performance for several domains and was administered across sites in COGS-1 and COGS-2. Most tests were included in both studies. COGS-1 included 328 patients with SZ and 497 healthy comparison subjects (HCS) and COGS-2 included 1195 patients and 1009 HCS. RESULTS: Demographically, COGS-1 participants were younger, more educated, with more educated parents and higher estimated IQ compared to COGS-2 participants. After controlling for demographics, the two samples produced very similar performance profiles compared to their respective controls. As expected, performance was better and with smaller effect sizes compared to controls in COGS-1 relative to COGS-2. Better performance was most pronounced for spatial processing while emotion identification had large effect sizes for both accuracy and speed in both samples. Performance was positively correlated with functioning and negatively with negative and positive symptoms in both samples, but correlations were attenuated in COGS-2, especially with positive symptoms. CONCLUSIONS: Patients ascertained through family-based design have more favorable demographics and better performance on some neurocognitive domains. Thus, studies that use case-control ascertainment may tap into populations with more severe forms of illness that are exposed to less favorable factors compared to those ascertained with family-based designs.

Robust differences in antisaccade performance exist between COGS schizophrenia cases and controls regardless of recruitment strategies.

The impaired ability to make correct antisaccades (i.e., antisaccade performance) is well documented among schizophrenia subjects, and researchers have successfully demonstrated that antisaccade performance is a valid schizophrenia endophenotype that is useful for genetic studies. However, it is unclear how the ascertainment biases that unavoidably result from recruitment differences in schizophrenia subjects identified in family versus case-control studies may influence patient-control differences in antisaccade performance. To assess the impact of ascertainment bias, researchers from the Consortium on the Genetics of Schizophrenia (COGS) compared antisaccade performance and antisaccade metrics (latency and gain) in schizophrenia and control subjects from COGS-1, a family-based schizophrenia study, to schizophrenia and control subjects from COGS-2, a corresponding case-control study. COGS-2 schizophrenia subjects were substantially older; had lower education status, worse psychosocial function, and more severe symptoms; and were three times more likely to be a member of a multiplex family than COGS-1 schizophrenia subjects. Despite these variations, which were likely the result of ascertainment differences (as described in the introduction to this special issue), the effect sizes of the control-schizophrenia differences in antisaccade performance were similar in both studies (Cohen's d effect size of 1.06 and 1.01 in COGS-1 and COGS-2, respectively). This suggests that, in addition to the robust, state-independent schizophrenia-related deficits described in endophenotype studies, group differences in antisaccade performance do not vary based on subject ascertainment and recruitment factors.

Reduction of nightmares and other PTSD symptoms in combat veterans by prazosin: a placebo-controlled study.

OBJECTIVE: Prazosin is a centrally active alpha(1) adrenergic antagonist. The authors' goal was to evaluate prazosin efficacy for nightmares, sleep disturbance, and overall posttraumatic stress disorder (PTSD) in combat veterans. METHOD: Ten Vietnam combat veterans with chronic PTSD and severe trauma-related nightmares each received prazosin and placebo in a 20-week double-blind crossover protocol. RESULTS: Prazosin (mean dose=9.5 mg/day at bedtime, SD=0.5) was superior to placebo for the three primary outcome measures: scores on the 1) recurrent distressing dreams item and the 2) difficulty falling/staying asleep item of the Clinician-Administered PTSD Scale and 3) change in overall PTSD severity and functional status according to the Clinical Global Impression of change. Total score and symptom cluster scores for reexperiencing, avoidance/numbing, and hyperarousal on the Clinician-Administered PTSD Scale also were significantly more improved in the prazosin condition, and prazosin was well tolerated. CONCLUSIONS: These data support the efficacy of prazosin for nightmares, sleep disturbance, and other PTSD symptoms.

Prazosin reduces nightmares in combat veterans with posttraumatic stress disorder.

BACKGROUND: Preclinical and clinical observations suggest that the centrally active alpha1-adrenergic antagonist prazosin might alleviate trauma content nightmares and other symptoms in combat veterans with chronic posttraumatic stress disorder (PTSD). METHOD: In this retrospective chart review study, we analyzed data from 59 consecutive combat veterans with previously treatment-resistant chronic PTSD (DSM-IV criteria) and severe intractable trauma content nightmares to whom prazosin had been prescribed. Nightmare severity was quantified using the recurrent distressing dreams item of the Clinician Administered PTSD Scale (CAPS). Change in overall PTSD severity exclusive of nightmares was estimated by assigning a Clinical Global Impressions-Change scale (CGI-C) score based on chart review. RESULTS: Mean +/- SEM recurrent distressing dreams item scores improved significantly (7.0 +/- 0.2 to 3.5 +/- 0.3, p <.0001) in the 36 patients who completed at least 8 weeks of prazosin treatment at their maximum titrated dose. The mean maximum prazosin dose achieved in these 36 patients was 9.6 +/- 0.9 mg/day. Recurrent distressing dreams scores also improved in the total group who filled their prazosin prescriptions (N = 51) (7.1 +/- 0.2 to 4.2 +/- 0.3, p <.0001). In a comparison group of 8 patients who did not fill their prazosin prescriptions but continued in outpatient treatment, there was no significant change in CAPS recurrent distressing dreams score (6.8 +/- 0.5 to 6.7 +/- 0.4). There also was at least some improvement in CGI-C ratings of overall PTSD severity exclusive of nightmares in a substantial majority of patients receiving prazosin, but not in the 8 comparison subjects. There were no serious adverse effects attributable to prazosin. CONCLUSION: These observations suggest that prazosin may relieve symptomatic distress in PTSD, and they provide rationale for placebo-controlled trials of prazosin for PTSD trauma content nightmares and other PTSD symptoms.

Validation of the PTSD checklist in an HMO sample of women.

Although Post-traumatic Stress Disorder (PTSD) is common among patients seeking care at medical clinics, little is known about the performance of screening instruments for this disorder in these settings. Previous studies of acute trauma populations using the PTSD Checklist (PCL) have suggested that scores of 45-50 provide the best discrimination between cases and noncases. We gave the PCL to 1,225 randomly selected women enrolled in an HMO. After interviewing a sample of 261 of these women using a structured, clinician-administered PTSD interview, we compared the results of the PCL to the clinician interviews over a range of possible cut scores using Receiver Operating Characteristic analysis. The optimum balance of sensitivity and specificity for this population was a score of 30, yielding a sensitivity of.82 and specificity of.76. The positive and negative likelihood ratios for this cut score were 3.40 and 0.24, respectively. By comparison, the use of 45 as a cut score would result in very low sensitivity (.36) in this setting. The lower cut score found in this study may indicate that the use of previously published cut scores of 45-50 may not optimize the function of the PCL as a screening tool outside of acute trauma settings due to an unacceptably high number of false negative cases.

Screening for post-traumatic stress disorder in female Veteran's Affairs patients: validation of the PTSD checklist.

We evaluated the screening validity of a self-report measure for post traumatic stress disorder (PTSD), the PTSD Checklist (PCL), in female Veterans Affairs (VA) patients. All women seen for care at the VA Puget Sound Health Care system from October 1996-January 1999 (n=2,545) were invited to participate in a research interview. Participants (n=282) completed the 17-item PCL, followed by a gold standard diagnostic interview for PTSD, the Clinician Administered PTSD Scale (CAPS). Thirty-six percent of the participants (n=100) met CAPS diagnostic criteria for current PTSD. Receiver Operating Characteristic (ROC) analysis was used to evaluate the screening performance of the PCL. The area under the ROC curve was 0.86 (95% CI 0.82-0.90). A PCL score of 38 optimized the performance of the PCL as a screening test (sensitivity 0.79, specificity 0.79). The PCL performed well as a screening measure for the detection of PTSD in female VA patients.

Screening for substance abuse and psychiatric disorders among women patients in a VA Health Care System.

OBJECTIVE: This study of women Veterans Affairs (VA) health care patients screened for the prevalence of past-year smoking, hazardous and problem drinking, other drug abuse, and psychiatric disorders. METHODS: A survey was mailed to women veterans who had received care from VA Puget Sound Health Care System between October 1, 1996, and January 1, 1998. Screening measures included questions about cigarettes; questions from the Alcohol Use Disorders Identification Test about consumption (hazardous drinking); the TWEAK test (problem drinking); a drug abuse screen; the Patient Health Questionnaire (psychiatric conditions); and the PTSD (posttraumatic stress disorder) Checklist. RESULTS: Of eligible patients, 1,257 (65 percent) returned surveys with complete substance use data. Patients reported a relatively high rate of past-year smoking (29.1 percent) and hazardous drinking, problem drinking, or both (31.1 percent). The rate of past-year drug use was much lower (4.9 percent). Younger age was strongly associated with greater substance abuse: 59 percent of women under age 35 screened positive for smoking, hazardous or problem drinking, or drug abuse. Screening positive for a psychiatric condition (N=504) was also associated with substance abuse: The rate of past-year drug abuse among women screening positive for a psychiatric condition (9.7 percent) was double the rate for the entire sample. Of the women who screened positive for depression, PTSD, eating disorders, or panic disorders, 57 percent screened positive for substance abuse (including smoking). CONCLUSIONS: Substance abuse is common among women VA patients and is associated with younger age and with screening positive for other psychiatric conditions. Providers are expected to follow up on positive screening tests, and these data indicate substantial provider burden.

Is there an association between advanced paternal age and endophenotype deficit levels in schizophrenia?

The children of older fathers have increased risks of developing schizophrenia spectrum disorders, and among those who develop these disorders, those with older fathers present with more severe clinical symptoms. However, the influence of advanced paternal age on other important domains related to schizophrenia, such as quantitative endophenotype deficit levels, remains unknown. This study investigated the associations between paternal age and level of endophenotypic impairment in a well-characterized family-based sample from the Consortium on the Genetics of Schizophrenia (COGS). All families included at least one affected subject and one unaffected sibling. Subjects met criteria for schizophrenia (probands; n = 293) or were unaffected first-degree siblings of those probands (n = 382). Paternal age at the time of subjects' birth was documented. Subjects completed a comprehensive clinical assessment and a battery of tests that measured 16 endophenotypes. After controlling for covariates, potential paternal age-endophenotype associations were analyzed using one model that included probands alone and a second model that included both probands and unaffected siblings. Endophenotype deficits in the Identical Pairs version of the 4-digit Continuous Performance Test and in the Penn Computerized Neurocognitive Battery verbal memory test showed significant associations with paternal age. However, after correcting for multiple comparisons, no endophenotype was significantly associated with paternal age. These findings suggest that factors other than advanced paternal age at birth may account for endophenotypic deficit levels in schizophrenia.