Accounting for genotyping errors in tagging SNP selection.

One limitation of the existing tagging SNP selection algorithms is that they assume the reported genotypes are error free. However, genotyping errors are often unavoidable in practice. Many tagging SNP selection methods depend heavily on the estimated haplotype frequencies. Recent studies have demonstrated that even slight genotyping errors can lead to serious consequences with regard to haplotype reconstruction and frequency estimation. Here we present a tagging SNP selection method that allows for genotyping errors. Our method is a modification of the pair-wise r(2) tagging SNP selection algorithm proposed by Carlson et al. (2004). We have replaced the standard EM algorithm in Carlson's method with an EM that accounts for genotyping errors, in an attempt to obtain better estimates of the haplotype frequencies and r(2) measure. Through simulation studies we compared the performance of our modified algorithm with that of the original algorithm. We found that the number of tags selected by both methods increased with increasing genotyping errors, though our method led to smaller increase. The power of haplotype association tests using the selected tags decreased dramatically with increasing genotyping errors. The power of single marker tests also decreased, but the reduction was not as much as the reduction in power of haplotype tests. When restricting the mean number of tags selected by both methods to be similar to the baseline number, Carlson's method and our method led to similar power for the subsequent haplotype and single marker tests. Our results showed that, by accounting for random genotyping errors, our method can select tagging SNPs more efficiently than Carlson's method. The computer program that implements our modified tagging SNP selection algorithm is available at our web site: http://www.personal.psu.edu/tuy104/.

Acute and chronic effects of developmental iron deficiency on mRNA expression patterns in the brain.

Because of the multiple biochemical pathways that require iron, iron deficiency can impact brain metabolism in many ways. The goal of this study was to identify a molecular footprint associated with ongoing versus long term consequences of iron deficiency using microarray analysis. Rats were born to iron-deficient mothers, and were analyzed at two different ages: 21 days, while weaning and iron-deficient; and six months, after a five month iron-sufficient recovery period. Overall, the data indicate that ongoing iron deficiency impacts multiple pathways, whereas the long term consequences of iron deficiency on gene expression are more limited. These data suggest that the gene array profiles obtained at postnatal day 21 reflect a brain under development in a metabolically compromised setting that given appropriate intervention is mostly correctable. There are, however, long term consequences to the developmental iron deficiency that could underlie the neurological deficits reported for iron deficiency.

Care of patients with chronic mental illness: comparison of home and half-way house care.

Community-based services are being developed as mental health services. The purpose of this study was to examine the effect between home care and half-way house services on patients with schizophrenia. The design was quasi-experimental and used repeated measurements. There were 60 subjects, 37 receiving home care and 23 receiving half-way house care which were affiliated with one general hospital in the south of Taiwan. Of the 60 chronic schizophrenic patients, there were 34 males and 26 females with an average age of 34 years. The Quality of Life Scale was applied to measure each patient four times, at an interval of two months. These follow-up data were analyzed by Generalized Estimating Equation-I (GEE-I) because repeated observations on an individual may be correlated. The result showed that the total QOL in patients receiving home care programs was significantly higher than those receiving half-way house service. The total scores of QOL in patients under half-way house and home care services did not show secular change. The patients under home care program showed a somewhat improvement for a short period of time. However, as time went on, the patients showed no obvious improvement in their life quality. The dimensions of independence and social activity in QOL also showed significantly different between these two groups. The results may provide guides on designing programs and activities for the chronic mental patients. However, the best decision to apply which program for patients need continouous and comprehensive assessment.

Familial risk ratio of sarcoidosis in African-American sibs and parents.

While sarcoidosis is thought to aggregate in families, little is known about the risk to relatives of sarcoidosis patients. To estimate the familial risk ratio (lambda) of sarcoidosis in sibs and parents of cases, the authors studied 179 African-American families ascertained through an index sarcoidosis case diagnosed at Henry Ford Hospital in Detroit, Michigan. Among those relatives enrolled between 1997 and 1999, 12 of 327 (3.7%) sibs and 11 of 161 (6.8%) parents reported a history of sarcoidosis. The lambda in this sample of relatives, estimated by computing an age, sex, and race standardized incidence ratio, was 2.24 (95% confidence interval: 1.16, 3.92) for sibs and 2.82 (95% confidence interval: 1.41, 5.05) for parents. For sibs and parents combined, lambda was 2.49 (95% confidence interval: 1.58, 3.73). Results stratified by proband characteristics indicated that lambda was greater for relatives of younger (lambda = 2.93, 95% confidence interval: 1.52, 5.12) and male (lambda = 3.98, 95% confidence interval: 1.99, 7.12) probands. A higher lambda was also found for male family members and sibs born later in the birth order. A Monte Carlo method was also used to estimate lambda, with similar results obtained. Overall, these results indicate that, in African Americans, sibs and parents of sarcoidosis cases have about a 2.5-fold increased risk for sarcoidosis and that heterogeneity in disease risk may exist among family members.

Use of weighted p-values in regional inference procedures.

Our previous studies have demonstrated that the power to detect linkage was improved by calculating a moving average of consecutive p-values in a small region as compared with testing all single p-values. The goal of this study was to test whether the power can be improved further with an alternative method whereby the middle p-values in the sequence were given more weight than the others. We also wanted to compare the moving average tests with multipoint linkage tests. The simulated extended pedigree data from the general population was analyzed to identify two major genes (MG1 and MG5) underlying two quantitative traits (Q1 and Q5). We used the variance components method implemented in the GENEHUNTER program to test for linkage of 14-marker regions each on chromosome 19 and chromosome 1 to the adjusted quantitative traits Q1 and Q5, respectively, in all 50 replicates. As before, we found that the moving average test was more powerful than a test based on single p-values. In some cases, the weighting procedure increased the power further and was similar to that of multipoint analysis, but this was not consistently found. In addition, all methods had low power and it is not possible to make a general conclusion that some weighting schemes are better than others.

Insurance and education determine survival in infantile coarctation of the aorta.

Health outcomes are determined by case severity, physician decisions, and patient variables. In a population-based study between 1981 and 1989, 103 cases of infant coarctation of the aorta were diagnosed before one year of age. The goal of this study was to determine whether patient race, gender, income, and insurance status had effects on outcome of coarctation of the aorta that were distinct from the effect of case severity. Survival of infants with coarctation of the aorta, a common congenital cardiovascular malformation, is associated with greater maternal education and with having any health insurance but not with measures of severity. Infants without health insurance are 12.8 times more likely to die than infants with any health insurance. Fifty-five percent of all deaths in infant coarctation occur prior to surgical treatment. One-third of deaths occur without diagnosis. Outcome measures require knowledge of the entire population and of insurance status to inform policy.

Inhibitors of hydroxymethylglutaryl-coenzyme A reductase and risk of fracture among older women.

BACKGROUND: Inhibitors of hydroxymethylglutaryl-coenzyme A reductase (statins) increase new bone formation in rodents and in human cells in vitro. Statin use is associated with increased bone mineral density of the femoral neck. We undertook a population-based case-control study at six health-maintenance organisations in the USA to investigate further the relation between statin use and fracture risk among older women. METHODS: We investigated women aged 60 years or older. Exposure, outcome, and confounder information was obtained from automated claims and pharmacy data from October, 1994, to September, 1997. Cases had an incident diagnosis of non-pathological fracture of the hip, humerus, distal tibia, wrist, or vertebrae between October, 1996, and September, 1997. Controls had no fracture during this period. We excluded women with records of dispensing of drugs to treat osteoporosis. FINDINGS: There were 928 cases and 2747 controls. Compared with women who had no record of statin dispensing during the previous 2 years, women with 13 or more statin dispensings during this period had a decreased risk of non-pathological fracture (odds ratio 0.48 [95% CI 0.27-0.83]) after adjustment for age, number of hospital admissions during the previous year, chronic disease score, and use of non-statin lipid-lowering drugs. No association was found between fracture risk and fewer than 13 dispensings of statins or between fracture risk and use of non-statin lipid-lowering drugs. INTERPRETATION: Statins seem to be protective against non-pathological fracture among older women. These findings are compatible with the hypothesis that statins increase bone mineral density in human beings and thereby decrease the risk of osteoporotic fractures.

Assessment of estimation procedures for risk and onset hazard with dependent data.

Analysis of the role of candidate genes as risk factors for age-dependent hereditary conditions often ignores the importance of dependence among sibships or other family clusters for age of onset. We examined the performance of several methods of survival analysis with dependent data using Collaborative Study on the Genetics of Alcoholism families as submitted for GAW11. Additionally, an arbitrary truncation of cluster size was performed to explore the potential impact of heterogeneity of family size on the resulting inferences concerning the role of candidate genes. Our results showed substantial differences in attribution of risk to candidate genes according to whether the method utilized allowed for dependence in onset age and according to whether the sample was truncated or arbitrarily stratified. Further work needs to be done to clarify the importance of properly accounting for dependent data in age-dependent phenotypes and in integrating these methods into widely used genetic analysis computer programs.

Comparison of two linkage inference procedures for genes related to the P300 component of the event related potential.

Our goal was to detect genes contributing to the P300 component of the event related potential (ERP). We found that all of the ERP traits were highly correlated. Most of them distinguished alcoholics from nonalcoholics. To have one summary variable for the ERP traits, we calculated the first principal component (PRIN1). After adjusting for age and sex, we screened for linkage of PRIN1 to all of the markers using the two-point Haseman-Elston sib-pair test. We compared results obtained from computing a moving average of two-point p-values ("regional" inference) in an approximately 10 cM region with those obtained from single, two-point tests. Different "suggestive" and "significant" linkage regions were found using the two methods. Based on the regional method, areas on chromosomes 2 and 5 should be followed up in future studies.

Regional inference with averaged P values increases the power to detect linkage.

Controversy exists with respect to the choice of an appropriate critical value when testing for linkage in a genomic screen. A number of critical values have been proposed for single-locus and multi-locus linkage analyses. In this study, criteria based on multiple single-locus analyses (i.e., regional test criteria) are evaluated using simulation methods for three different map densities. Tests based on single loci, multiple consecutive single loci, and moving averages of consecutive single loci are considered. Appropriate critical values are determined based on results from simulations under the null hypothesis of no linkage. The power of each "regional test " was compared to the power of a single-locus test. Results suggest that the best power was found when averaging P values over an interval size of 9-15 cM, and that testing the average of P values from two consecutive loci is superior to testing each single locus separately. The increase in power ranged from 7- 29% over the simulations considered.

A comparison of the reliability of two techniques of left double-lumen tube bronchial cuff inflation in producing water-tight seal of the left mainstem bronchus.

UNLABELLED: A double-lumen endobronchial tube (DLT) bronchial cuff inflation technique that reliably ensures effective water-tight isolation of the two lungs has not been determined. In this study, 20 patients undergoing thoracic surgery requiring a left DLT had the bronchial cuff of the DLT inflated by one of two techniques. In Group 1, the cuff was inflated to produce an air-tight seal of the left bronchus using the underwater seal technique. In Group 2, the cuff was inflated to a pressure of 25 cm H2O. After bronchial cuff inflation in both groups, water-tight bronchial seal was tested by instilling 2 mL of 0.01% methylene blue (MB) above the bronchial cuff of the DLT. Fifteen minutes later, fiberoptic bronchoscopy was performed via the bronchial lumen of the DLT to determine whether MB had seeped past the bronchial cuff. Cuff volume was 0.75+/-0.64 and 0.76+/-0.46 mL, cuff pressure was 30.1+/-27.0 and 25.0+/-0.0 cm H2O (mean+/-SD), and MB was positively identified in two and five patients in Groups 1 and 2, respectively. The difference in cuff volume and pressure and the higher MB seepage in Group 2 compared with Group 1 was not statistically significant. In both groups, MB seepage occurred only when the bronchial cuff volume was <1 mL and when the patients were positioned in the left lateral decubitus position. These findings suggest that the risk of aspiration is greatest when the DLT is positioned in the dependent lung and when the bronchial cuff volume is <1 mL. IMPLICATIONS: Water-tight sealing of the left bronchus by DLT bronchial cuff was tested after cuff inflation using two different techniques. Neither air-tight bronchial seal nor cuff pressure of 25 cm H2O guaranteed protection against aspiration. The risk of aspiration was greatest when the DLT was positioned in the dependent lung and when the bronchial cuff volume was < 1 mL.

Fatigue in HIV-infected men receiving investigational interleukin-2.

BACKGROUND: Although fatigue is an almost universal clinical complaint of people with human immunodeficiency virus (HIV) infection, little has been done to study systematically the etiology, frequency, severity, response to, or management of HIV-related fatigue. In addition, HIV-related treatments may contribute to fatigue. OBJECTIVES: To describe the extent and severity of perceived fatigue in a cohort of HIV-infected men (N= 50) who, as participants in a randomized clinical trial, were randomized to receive or not to receive investigational interleukin-2 (IL-2). METHOD: A modified Piper Fatigue Scale was used to measure fatigue at baseline, at the end of 5 days of IL-2 therapy, 1 week later at home, and 1 month later for three consecutive cycles of IL-2 therapy. RESULTS: Against a variable background of baseline fatigue in all subjects, those receiving IL-2 reported a significant increase in their level of fatigue after receiving IL-2. Fatigue levels remained elevated 1 week later but returned to baseline by 1 month. Fatigue was related to the dose of IL-2 but not to the reported amount or quality of sleep. CONCLUSIONS: Against a background of fatigue related to HIV infection and its multiple manifestations and treatments, therapy with IL-2 dramatically increases the experience of fatigue. Although this increase is transient and tends to return to baseline by 1 month, during that month the patient's life function and quality may be severely affected.

Comparison of results and risk factors of cardiac surgery in two 3-year time periods in the 1990s.

With the increasing number of treatment options for heart disease, decision-making requires profiles of risk for conventional cardiac surgery. Refinements in techniques and clinical practices seem to have reduced surgical risk. This study was performed to determine current risk factors. From July 1, 1990, to June 30, 1996, 1,036 consecutive patients underwent 1,042 heart operations using standard incisions and cardiopulmonary bypass with cardioplegia. Univariate and multivariate analyses using a logistic regression model were performed to determine factors significant for combined 30-day and hospital mortality. To determine if there were trends in the results and the risk factors, the last 500 consecutive cases in the series were analyzed separately. Overall, 30-day mortality was 17 of 1,042 (1.6%) and combined 30-day and hospital mortality was 27 of 1,042 (2.6%). Significant risk factors for combined 30-day and hospital mortality by multivariate analyses were: emergent/resuscitative status, preoperative dialysis, left ventricular ejection fraction < or = 30%, valve operation, and creatinine > or = 1.5 mg/dl. Comparison with baseline characteristics of the patients undergoing the last 500 consecutive operations to the earlier 542 operations in the study group showed that risk factors had a very similar profile for the 2 groups. The overall 30-day mortality for the last 500 consecutive operations was 5 of 500 (1.0%) and combined 30-day and hospital mortality was 8 of 500 (1.6%). The significant risk factors by multivariate analyses were reduced to left ventricular ejection fraction < or = 30% and creatinine > or = 1.5 mg/dl. These results indicate that modern techniques and clinical practices have mitigated well-recognized risk factors in conventional cardiac surgery and this trend is ongoing.

Disability and psychiatric disorders in an urban community: measurement, prevalence and outcomes.

BACKGROUND: The purpose of this analysis was to examine: (1) the prevalence of psychiatric disorders among disabled people, using seven different measures of disability; (2) variation in disability between and within psychiatric diagnostic categories; and (3) relationship of diagnosis and disability to health service utilization. METHOD: Data were drawn from Phase I and Phase II of the Eastern Baltimore Mental Health Survey, part of the Epidemiologic Catchment Area Program (ECA) conducted in 1980-1 to survey mental morbidity within the adult population. A total of 810 individuals received both a household interview and a standardized clinical psychiatric evaluation. Estimated prevalence rates were computed using appropriate survey sampling weights. RESULTS: Prevalence of disability ranged from 2.5 to 19.5%, varying with specific disability measure. Among those classified as disabled by any of the measures examined, 56 to 92% had a psychiatric disorder and serious chronic medical conditions were present in the majority of these cases (54 to 78%). Disability was expressed differently among the various diagnostic groups. Diagnostic category and disability were significant independent predictors of medical service utilization and receipt of disability payments. CONCLUSIONS: The majority of disabled adults living in the community have diagnosable psychiatric disorders, with the majority of these individuals suffering from significant chronic medical conditions as well, thus making co-morbidity the norm.

Hydrochlorothiazide is superior to isradipine for reduction of left ventricular mass: results of a multicenter trial. The Isradipine Study Group.

OBJECTIVES: We sought to determine the efficacy of isradipine in reducing left ventricular (LV) mass and wall thickness in hypertensive patients. BACKGROUND: LV hypertrophy on the echocardiogram is a strong predictor of cardiovascular events. Reduction of LV mass may be a desirable goal of drug therapy for hypertension. However, although thiazide diuretic drugs have been advocated as first-line therapy for hypertension, their efficacy in reducing LV mass has been questioned. METHODS: Patients with mild to moderate diastolic hypertension and LV mass in excess of 1 SD of normal values were randomized to isradipine (n = 89) or hydrochlorothiazide therapy (n = 45). Evaluations were obtained at baseline, after 3 and 6 months of treatment and 2 weeks after treatment was stopped. RESULTS: At 6 months, LV mass decreased by 43 +/- 45 g (mean +/- SD) with hydrochlorothiazide (p < 0.001) but only by 11 +/- 48 g with isradipine (p = NS; between-group comparison, p < 0.001). Two weeks after drug therapy was stopped, LV mass remained 24 +/- 41 g lower than that at baseline in the hydrochlorothiazide group (p = 0.003) but only 7 +/- 50 g lower in the isradipine group (p = NS). Septal and posterior wall thicknesses were significantly and equally reduced with both isradipine and hydrochlorothiazide. Greater LV mass reduction with hydrochlorothiazide was related to a 2.8 +/- 3.3-mm reduction of LV cavity size with hydrochlorothiazide but no reduction with isradipine. At 6 months of treatment, diastolic blood pressure (BP) by design was equally reduced in both treatment groups. At 3 months, systolic BP was reduced by 17 +/- 15 mm Hg with isradipine and by 26 +/- 15 and 25 +/- 17 mm Hg at 3 and 6 months, respectively, with hydrochlorothiazide (p = 0.003, between-group comparison). However, on stepwise multivariable regression analysis, treatment selection (partial r2 = 0.082, p = 0.001), change in average 24-h systolic BP (partial r2 = 0.032, p = 0.029) and change in average sitting systolic BP (partial r2 = 0.017, p = 0.096) were predictive of LV mass reduction. CONCLUSIONS: Despite an equivalent reduction of diastolic BP, 6 months of therapy with hydrochlorothiazide is associated with a substantial reduction of LV mass, greater than that with isradipine. The superior efficacy of hydrochlorothiazide for LV mass reduction is associated with a greater reduction of systolic BP as well as drug selection itself. These data may have important therapeutic implications.

True and false positive peaks in genomewide scans: applications of length-biased sampling to linkage mapping.

Disease-susceptibility loci are now being mapped via genomewide scans in which a linkage statistic is computed at each of a large number of markers. Such disease-susceptibility loci may be identified via a peak in the test statistic when the latter is plotted against the genetic map. In this paper we establish, by appealing to renewal theory, that true positive peaks are expected to be longer than false positive peaks. These results are verified by a realistic simulation of a genomewide linkage study based on the affected-sib-pair design. Since longer peaks are more likely to contain a gene of interest than are shorter peaks, these differences may aid in linkage mapping, justifying assignment of lower priority to shorter peaks. However, since these differences are generally small, statistics based on both peak length and height may not be much more powerful than those based on height alone. The results presented here also provide a theoretical framework for methods that use the length of shared haplotypes in populations to map disease genes.

Risks of cardiac operations for elderly patients: reduction of the age factor.

BACKGROUND: Age has been considered an important risk factor for cardiac operations. Recent refinements have been designed to reduce cardiac, neurologic, and renal complications. METHODS: Analysis of cardiac surgical outcomes including mortality, length of stay, complications, and costs were undertaken for a consecutive series of 285 patients 70 years old and older and 568 patients younger than 70 years who underwent operation during 1991 through 1995. Management included antegrade and retrograde cold and warm blood cardioplegia, epicardial echocardiography, retrosternal dissection for reoperations, maintenance of "normal" arterial pressure, and measures to avoid renal dysfunction. Parsonnet risk stratification and multiple regression were used to account for risk factors. RESULTS: The 30-day mortality rate for elderly patients was 1.8% (5/285) and 1.8% (10/568) for patients less than 70 years old (p = not significant). The hospital mortality rate for the elderly patients was 3.2% (9/285) versus 2.5% (14/568) for the younger group (p = not significant). The frequencies of complications were not different. Over the 5-year period, length of stay decreased from 12.5 +/- 1.5 days to 8.9 +/- 0.9 days for patients 70 years old and older and from 11.5 +/- 0.1 to 6.4 +/- 0.3 days for patients less than 70 years old. Hospital charges for the elderly group were 13% higher. CONCLUSIONS: Modern cardiac surgical techniques and clinical practices have reduced the importance of the age factor.

Quantitative MRI volume changes in late onset schizophrenia and Alzheimer's disease compared to normal controls.

Volumes of medial and lateral temporal lobe structures were assessed using magnetic resonance imaging (MRI) in 11 patients with late-life onset schizophrenia (LOS), 18 normal elderly controls and 12 patients with moderate cognitive impairment due to Alzheimer's disease (AD) who had no non-cognitive symptoms. While both patient groups had smaller volumes of several medial temporal regions (e.g. entorhinal cortex, left hippocampus), schizophrenics had significantly smaller anterior superior temporal gyri (STG) than normal controls, but AD patients did not. We have previously demonstrated anterior STG volume to be reduced in early life onset schizophrenia.

Ziskind-Somerfeld Research Award 1996. Medial and superior temporal gyral volumes and cerebral asymmetry in schizophrenia versus bipolar disorder.

Prior magnetic resonance imaging (MRI) studies report both medial and lateral cortical temporal changes and disturbed temporal lobe asymmetries in schizophrenic patients compared with healthy controls. The specificity of temporal lobe (TL) changes in schizophrenia is unknown. We determined the occurrence and specificity of these TL changes. Forty-six schizophrenic patients were compared to 60 normal controls and 27 bipolar subjects on MRI measures of bilateral volumes of anterior and posterior superior temporal gyrus (STG), amygdala, entorhinal cortex, and multiple medial temporal structures, as well as global brain measures. Several regional comparisons distinguished schizophrenia from bipolar disorder. Entorhinal cortex, not previously assessed using MRI in schizophrenia, was bilaterally smaller than normal in schizophrenia but not in bipolar disorder. Schizophrenic but not bipolar patients had an alteration of normal posterior STG asymmetry. Additionally, left anterior STG and right amygdala were smaller than predicted in schizophrenia but not bipolar disorder. Left amygdala was smaller and right anterior STG larger in bipolar disorder but not schizophrenia.