Joseph Erdos

Regulation of G proteins by chronic morphine in the rat locus coeruleus

A possible role for G proteins in contributing to the chronic actions of opiates was investigated in the rat locus coeruleus (LC). The LC is a relatively homogeneous brain region that appears to play an important role in mediating acute and chronic opiate action in animals, as well as in humans. It was found that chronic, but not acute, treatment of rats with morphine, under conditions known to induce states of opiate tolerance and dependence, produced an increase in the level of pertussis toxin-mediated ADP-ribosylation of G proteins in the LC. The morphine-induced increase in ADP-ribosylation occurred in both Gi and Go, and was observed over a 30-fold range of NAD concentrations used. Concomitant treatment of rats with the opiate receptor antagonist naltrexone blocked the ability of morphine to produce this effect. In contrast, chronic morphine had no effect on pertussis toxin-mediated ADP-ribosylation of Gi and Go in the other brain regions studied, including the neostriatum, frontal cortex, and dorsal raphe. Chronic morphine also had no effect on cholera toxin-mediated ADP-ribosylation of Gs in the LC and these other brain regions. Preliminary immunoblot analysis revealed that increased ADP-ribosylation levels of the alpha subunit of Go in the LC were associated with equivalent increases in the immunoreactivity of this protein in this brain region. It is possible that the observed regulation of G-proteins by morphine in the LC represents part of the changes that underlie opiate addiction in these neurons.

Gender Differences in Rates of Depression, PTSD, Pain, Obesity, and Military Sexual Trauma Among Connecticut War Veterans of Iraq and Afghanistan

PURPOSE The current wars in Iraq and Afghanistan have led to an increasing number of female veterans seeking medical and mental healthcare in the Department of Veterans Affairs (VA) healthcare system. To better understand gender differences in healthcare needs among recently returned veterans, we examined the prevalence of positive screenings for depression, posttraumatic stress disorder (PTSD), military sexual trauma (MST), obesity, and chronic pain among female and male veterans of Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) receiving care at the VA Connecticut Healthcare System. METHODS We performed a retrospective, cross-sectional data analysis of OEF/OIF veterans at VA Connecticut who received services in either Primary Care or the Womens Health Clinic between 2001 and 2006. RESULTS In this study, 1129 electronic medical records (1032 men, 197 women) were examined. Female veterans were more likely to screen positive for MST (14% vs. 1%, p < 0.001) and depression (48% vs. 39%, p = 0.01) and less likely to screen positive for PTSD (21% vs. 33%, p = 0.002). There was no significant gender difference in clinically significant pain scores. Men were more likely than women to have body mass index (BMI) >30 kg/m(2) (21% vs. 13%, p = 0.008). CONCLUSIONS These results suggest that important gender differences exist in the prevalence of positive screenings for MST, depression, obesity, and PTSD. As the VA continues to review and improve its services for women veterans, clinicians, researchers, and senior leaders should consider innovative ways to ensure that female veterans receive the health services they need within the VA system.

Exploring performance issues for a clinical database organized using an entity-attribute-value representation.

BACKGROUND The entity-attribute-value representation with classes and relationships (EAV/CR) provides a flexible and simple database schema to store heterogeneous biomedical data. In certain circumstances, however, the EAV/CR model is known to retrieve data less efficiently than conventionally based database schemas. OBJECTIVE To perform a pilot study that systematically quantifies performance differences for database queries directed at real-world microbiology data modeled with EAV/CR and conventional representations, and to explore the relative merits of different EAV/CR query implementation strategies. METHODS Clinical microbiology data obtained over a ten-year period were stored using both database models. Query execution times were compared for four clinically oriented attribute-centered and entity-centered queries operating under varying conditions of database size and system memory. The performance characteristics of three different EAV/CR query strategies were also examined. RESULTS Performance was similar for entity-centered queries in the two database models. Performance in the EAV/CR model was approximately three to five times less efficient than its conventional counterpart for attribute-centered queries. The differences in query efficiency became slightly greater as database size increased, although they were reduced with the addition of system memory. The authors found that EAV/CR queries formulated using multiple, simple SQL statements executed in batch were more efficient than single, large SQL statements. CONCLUSION This paper describes a pilot project to explore issues in and compare query performance for EAV/CR and conventional database representations. Although attribute-centered queries were less efficient in the EAV/CR model, these inefficiencies may be addressable, at least in part, by the use of more powerful hardware or more memory, or both.

Exploring the Degree of Concordance of Coded and Textual Data in Answering Clinical Queries from a Clinical Data Repository

OBJECTIVE To query a clinical data repository (CDR) for answers to clinical questions to determine whether different types of fields (coded and free text) would yield confirmatory, complementary, or conflicting information and to discuss the issues involved in producing the discrepancies between the fields. METHODS The appropriate data fields in a subset of a CDR (5,135 patient records) were searched for the answers to three questions related to surgical procedures. Each search included at least one coded data field and at least one free-text field. The identified free-text records were then searched manually to ensure correct interpretation. The fields were then compared to determine whether they agreed with each other, were supportive of each other, contained no entry (absence of data), or were contradictory. RESULTS The degree of concordance varied greatly according to the field and the question asked. Some fields were not granular enough to answer the question. The free-text fields often gave an answer that was not definitive. Absence of data was most logically interpreted in some cases as lack of completion of data and in others as a negative answer. Even with a question as specific as which side a hernia was on, contradictory data were found in 5 to 8 percent of the records. CONCLUSIONS Using the data in the CDR to answer clinical questions can yield significantly disparate results depending on the question and which data fields are searched. A database cannot just be queried in automated fashion and the results reported. Both coded and textual fields must be searched to obtain the fullest assessment. This can be expected to result in information that may be confirmatory, complementary, or conflicting. To yield the most accurate information possible, final answers to questions require human judgment and may require the gathering of additional information.

Measuring performance directly using the veterans health administration electronic medical record: a comparison with external peer review.

Background:Electronic medical records systems (EMR) contain many directly analyzable data fields that may reduce the need for extensive chart review, thus allowing for performance measures to be assessed on a larger proportion of patients in care. Objective:This study sought to determine the extent to which selected chart review-based clinical performance measures could be accurately replicated using readily available and directly analyzable EMR data. Methods:A cross-sectional study using full chart review results from the Veterans Health Administrations External Peer Review Program (EPRP) was merged to EMR data. Results:Over 80% of the data on these selected measures found in chart review was available in a directly analyzable form in the EMR. The extent of missing EMR data varied by site of care (P < 0.01). Among patients on whom both sources of data were available, we found a high degree of correlation between the 2 sources in the measures assessed (correlations of 0.89–0.98) and in the concordance between the measures using performance cut points (kappa: 0.86–0.99). Furthermore, there was little evidence of bias; the differences in values were not clinically meaningful (difference of 0.9 mg/dL for low-density lipoprotein cholesterol, 1.2 mm Hg for systolic blood pressure, 0.3 mm Hg for diastolic, and no difference for HgbA1c). Conclusions:Directly analyzable data fields in the EMR can accurately reproduce selected EPRP measures on most patients. We found no evidence of systematic differences in performance values among these with and without directly analyzable data in the EMR.

NOTCH4 gene haplotype is associated with schizophrenia in African Americans

BACKGROUND The goal of this study was to investigate the relationship between the NOTCH4 gene and schizophrenia in African American (AA) and European American (EA) subjects. METHODS Two single nucleotide polymorphisms (SNPs) at the NOTCH4 locus were genotyped in 123 AA schizophrenia patients, 223 EA schizophrenia patients, 85 AA healthy control subjects, and 211 EA healthy control subjects. The specific markers studied were -1725T/G and -25T/C. Comparisons of allele and haplotype frequencies between patients and control subjects were performed with the chi-square test, the Fishers Exact Test, and CLUMP software. Linkage disequilibrium (LD) between these two SNPs was calculated with the 3LOCUS program. RESULTS The haplotype -1725G/-25T associates to schizophrenia in AA subjects (p =.0008), but not in EA subjects. Alleles -1725G and allele -25T are in positive LD both in AAs and EAs. Allele and haplotype frequencies differ significantly between AAs and EAs. CONCLUSIONS The haplotype -1725G/-25T at the NOTCH4 locus, which results from SNPs of NOTCH4 that are in LD, may increase susceptibility to schizophrenia in AAs. Any effect of this locus on risk for schizophrenia is population-specific.

Association study of DTNBP1 with schizophrenia in a US sample.

Background Straub et al. (2002b) located a susceptibility region for schizophrenia at the DTNBP1 locus. At least 40 studies (including one study in US populations) attempted to replicate this original finding, but the reported findings are highly diverse and at least five pathways by which dysbindin protein might be involved in schizophrenia have been proposed. This study aimed to test the association in two common US populations by using powerful analytic methods. Methods Six markers at DTNBP1 were genotyped by mass spectroscopy (‘MassARRAY’ technique) in a sample of 663 individuals, including 346 healthy individuals European--Americans (EAs) and 48 African--Americans (AAs), and 317 individuals with schizophrenia (235 EAs and 82 AAs). Thirty-eight ancestry-informative markers were genotyped in this sample to infer the ancestry proportions. Diplotype, haplotype, genotype, and allele frequency distributions were compared between the cases and controls, controlling for possible population stratification, admixture, and sex-specific effects, and taking interaction effects into account, using a logistic regression analysis (an extended structured association method). Results Conventional case-control comparisons showed that genotypes of the markers P1578 (rs1018381) and P1583 (rs909706) were nominally associated with schizophrenia in EAs and in AAs, respectively. These associations became less or nonsignificant after controlling for population stratification and admixture effects (using structured association or regression analysis), and became nonsignificant after correction for multiple testing. However, regression analysis showed that the common diplotypes (ACCCTT/GCCGCC or GCCGCC/GCCGCC) and the interaction effects of haplotypes GCCGCC×GCCGCC significantly affected risk for schizophrenia in EAs, effects that were modified by sex. Fine-mapping using δ or J statistics located the specific markers (δ: P1328; J: P1333) closest to the putative risk sites in EAs. Conclusion This study shows that DTNBP1 is a risk gene for schizophrenia in EAs. Variation at DTNBP1 may modify risk for schizophrenia in this population.

Comparison of Two VA Laboratory Data Repositories Indicates That Missing Data Vary Despite Originating From the Same Source

Background:Assessing accuracy and completeness of data is an important component of conducting research. VA Healthcare System benefits from a highly developed electronic medical information system. The Immunology Case Registry was designed to monitor costs and quality of HIV care. The Decision Support System was developed to monitor utilization and costs of veterans in care. Because these systems extract data from the same source using independent methods, they provide an opportunity to compare the accuracy and completeness of each. Objective:To compare overlapping laboratory data from the Veterans Affairs Health Information System between 2 data repositories. Research Design:For hemoglobin, CD4+ lymphocyte counts (CD4), HIV RNA viral load, aspartate aminotransferase, alanine aminotransferase, glycosylated hemoglobin, creatinine, and white blood count, we calculated the percent of individuals with a value from each source. For results in both repositories, we calculated Pearsons correlation coefficients. Subjects:A total of 22,647 HIV+ veterans in the Virtual Cohort with a visit in fiscal year 2002. Results:For 6 out of 9 tests, 68% to 72% of the observations overlapped. For CD4, viral load, and glycosylated hemoglobin less than 31% of observations overlapped. Overlapping results were nearly perfectly correlated except for CD4. Conclusions:Six of the laboratory tests demonstrated remarkably similar amounts of overlap, though Immunology Case Registry and Decision Support System both have missing data. Findings indicate that validation of laboratory data should be conducted before its use in quality and efficiency projects. When 2 databases are not available for comparison, other methods of validation should be implemented.

CALCYON gene variation, schizophrenia, and cocaine dependence

Calcyon is a brain‐specific D1 dopamine receptor‐interacting protein, with a potential role in D1‐mediated physiological processes, including motor control, reward mechanisms, and cognitive processes. Our objective was to investigate the relationship between polymorphism of the CALCYON gene and (1) schizophrenia and (2) cocaine dependence in African‐American (AA) and European‐American (EA) subjects. Two single nucleotide polymorphisms (SNPs) at the CALCYON locus were genotyped in 70 AA and 206 EA individuals with schizophrenia and 90 AA and 118 EA individuals with cocaine dependence. The control group was comprised of 46 AA and 207 EA subjects screened to exclude those with psychiatric or substance use disorders. The specific polymorphisms studied were markers +295214G/A and +297151T/G. Comparisons of allele and haplotype frequencies between cases and controls were performed with the Fishers Exact Test. Linkage disequilibrium (LD) between these two SNPs was calculated with the 3LOCUS program. No alleles or haplotypes were found to be associated with schizophrenia or cocaine dependence either in AA or EA subjects. The markers +295214G/A and +297151T/G are in the same haplotype block in all subgroups. Allele and haplotype frequencies differed significantly between EA and AA subjects. These results suggest that these two genetic variants in the CALCYON gene do not play a major role in predisposition to either schizophrenia or cocaine dependence in AA or EA subjects. Furthermore, these findings begin to establish a haplotype map for this gene in the AA and EA populations.

The need for validation of large administrative databases: Veterans Health Administration ICD-9CM coding of exudative age-related macular degeneration and ranibizumab usage

We performed a validation study by chart review of data for exudative age-related macular degeneration (eAMD) and, because of the Veterans Administration (VA) therapy policy, ranibizumab usage in the largest electronic medical record system in the USA. We reviewed 5,854 distinct patients who visited an ophthalmology clinic within VA Connecticut from January 2006–December 2008. We randomly selected 98 of 138 distinct eAMD patients and 265 of 5,588 non-eAMD patients who did not receive ranibizumab. International Classification of Diseases, Ninth Revision, Clinical Modification coding of eAMD had an excellent positive predictive value of 97.8% (95% confidence interval (CI), 93.5–99.4%). The national Decision Support System (DSS) had an excellent positive predictive value of 100% (95% CI, 79.9–100%) for ranibizumab. However, the negative predictive value of the DSS dispensed ranibizumab decreased to 67.5 (95% CI, 62.1–72.4) because of a change in the way local values were stored that led to errors. Therefore, validation of clinical information over time in large databases is necessary.