Department of Biostatistics and Bioinformatics

Purpose The aim of this study was to assess the accuracy of a National Cancer Institute (NCI)-developed colorectal cancer screening questionnaire. Methods We conducted 36 cognitive interviews and made iterative changes to the questionnaire to improve comprehension. The revised questionnaire was administered face-to-face to 201 participants. The primary outcome was agreement between questionnaire responses and medical records for whether or not a participant was up-to-date for any colorectal cancer screening test. Results Comprehension of descriptions and questions was generally good; however, the barium enema description required several revisions. The sensitivity of the questionnaire for up-to-date screening status was 94%, specificity 63%, and concordance 88%. Conclusions The modified questionnaire was highly sensitive for determining if a person was up-to-date for any colorectal cancer screening test, although the specificity was low. Given the difficulty of obtaining all relevant records, self-report using this questionnaire is a reasonable option for identifying people who have undergone testing.

In the current system of allocation, patients awaiting orthotopic liver transplantation (OLT) remain at risk of developing de novo hepatocellular carcinoma (HCC) and removal from the waiting list. Using the United Network for Organ Sharing database, we calculated the rate and identified predictors of de novo HCC in patients listed for OLT between February 2002 and December 2004. Among 8566 patients, 1167 (13.6%) developed de novo HCC. Predictors of increased odds of de novo HCC were older age, male gender, Asian race, other race, hepatitis C, and hepatitis B. A sensitivity analysis of 2067 patients waiting at least 6 months found that 16.2% developed de novo HCC. Older age [odds ratio (OR) 1.05; 95% confidence interval (CI) 1.03, 1.07], male gender (OR 2.01; 95% CI 1.49, 2.71), Asian race (OR 2.39; 95% CI 1.20, 4.76), other race (OR 1.94; 95% CI 1.40, 2.68), hepatitis C (OR 2.36; 95% CI 1.76, 3.16), and hepatitis B (OR 1.96; 95% CI 1.19, 3.23) remained predictors of increased odds of de novo HCC, and alcoholic liver disease (OR 1.40; 95% CI 1.06, 1.86) emerged as a predictor of increased odds of de novo HCC. A significant proportion of patients listed for OLT develop de novo HCC. Identifying predictors of HCC in these patients may facilitate timely HCC screening and diagnosis. Liver Transpl 14:228–234, 2008. © 2008 AASLD.

Background Previous research reports that 48% of veterans regularly experience and express concern over pain. Outpatient service use is higher for veterans with pain than for veterans without pain. Our study objective was to identify differences in outpatient utilization between men and women veterans with chronic pain. Methods We identified all men and women veterans at the Durham Veterans Affairs Medical Center in fiscal year (FY) 2002 between the ages of 21 and 60 that had two visits for the same pain location at least 6 weeks apart as determined by ICD-9 coding. Men and women were age-matched at a 2:1 ratio. We then compared the number of outpatient visits between genders in FY 2003. Results We identified 406 female and 812 male veterans. The mean number of clinic visits for women was 25.2 (SD 30.2) and for men 17.6 (SD 24.1). After adjusting for multiple pain sites, psychiatric diagnoses, age, and comorbidities, women veterans had a 27% higher rate of outpatient visits than men (incidence rate ratio [RR] 1.27, 95% confidence [CI] 1.15 to 1.41). Specifically, women had higher rates of visits to primary care (RR 1.36, 95% CI 1.24 to 1.50), physical therapy (RR 1.67, 95% CI 1.20 to 2.33), and other clinics (RR 1.28, 95% CI 1.14 to 1.44), and had a higher rate of visits to address pain (RR 1.15, 95% CI 1.02 to 1.30) than men. Conclusions This is the first study to examine gender differences in chronic pain and utilization in the veteran population. Women veterans with chronic pain may need more resources to adequately manage chronic pain conditions as well as associated comorbidities and psychiatric disease.

Purpose: Treatment with cyclophosphamide (CYC) confers up to a 40% risk of ovarian failure in women of reproductive age. The use of GnRH agonists (GnRHa) to preserve ovarian function has been investigated in several small studies. We performed a systematic review of studies examining whether a GnRHa administered during chemotherapy is protective of ovarian function and fertility. Methods: We searched the English-language literature (1966( -April 2007 using MEDLINE and meeting abstracts and included studies that reported an association between GnRHa and ovarian preservation in women receiving chemotherapy. Studies without a control group were excluded. Ovarian preservation was defined as the resumption of menstrual cycles and a premenopausal follicle-stimulating hormone (FSH) after chemotherapy. Fertility was determined by a woman's ability to become pregnant. We estimated the summary relative risk (RR) and associated 95% confidence intervals (95% CI) using a random-effects model. Results: Nine studies included 366 women. Three studies included women with autoimmune disease receiving CYC; six included women with hematologic malignancy receiving combination chemotherapy. In total, 178 women were treated with GnRHa during chemotherapy, 93% of whom maintained ovarian function. Of the 188 women not treated with GnRHa, 48% maintained ovarian function. The use of a GnRHa during chemotherapy was associated with a 68% increase in the rate of preserved ovarian function compared with women not receiving a GnRHa (summary RR ¼ 1.68, 95% CI 1.34-2.1). Among the GnRHa-treated women, 22% achieved pregnancy following treatment compared with 14% of women without GnRHa therapy (summary RR ¼ 1.65, CI 1.03-2.6). Conclusions: Based on the available studies, GnRHa appear to improve ovarian function and the ability to achieve pregnancy following chemotherapy. Several randomized trials are underway to define the role and mechanism of GnRHa in ovarian function preservation. In the meantime, premenopausal women facing chemotherapy should be counseled about ovarian preservation options, including the use of GnRHa therapy.

The clinical course of patients with ALS is highly variable. While the median survival time from symptom onset is 2Á4 years, there are reports of survival ranging from less than a year to more than 40 years. Such variability makes planning difficult for patients and physicians, and complicates clinical trial design. We sought to validate previous predictors of survival and search for new ones using a large group of ALS patients in the National Registry of Veterans with ALS. We were especially interested in how various aspects of military service might affect survival. Subjects were those in the National Registry of Veterans with ALS who had probable or definite ALS (according to El Escorial criteria). A multivariable Cox proportional hazard regression model was used to examine variables for statistical association with ventilator-free survival time (determined from date of first diagnosis). Subjects who had not died or started ventilation by 31 October 2006 were censored. Our group of 1085 US military veterans with ALS was primarily male (98%) and white (94%), with mostly sporadic (95%) and extremity-onset (76%) ALS. Symptom onset occurred at a mean age of 59.3 years (60.6 years for diagnosis). Median survival time from symptom onset was 4.7 years (3.3 years from diagnosis). In our multivariable model, older age at diagnosis (HR 1.41 (95% CI 1.27Á1.55) per 10-year increase), non-extremity site of onset (HR 1.55 (1.24Á 1.94)), and past deployment to Vietnam (HR 1.73 (1.36Á2.19)) were all associated with shortened survival. A longer time to diagnosis was associated with better survival (HR 0.77 (0.70Á0.84) per one year increase in diagnosis time). In this unique cohort of veterans with ALS, traditional factors of reduced survival remained important. In addition, past deployment to Vietnam was found to be associated with shortened survival as well. This finding could be due to a common exposure, a shared characteristic, an unmeasured confounder, or an enrollment bias. More research will be needed to understand the reasons behind this new finding.

ObjectiveTo compare the ability of 3 database-derived comorbidity scores, the Charlson Score, Elixhauser method, and RxRisk-V, in predicting health service use among individuals with osteoarthritis (OA).To compare the ability of 3 database-derived comorbidity scores, the Charlson Score, Elixhauser method, and RxRisk-V, in predicting health service use among individuals with osteoarthritis (OA).MethodsThe study population comprised 306 patients who were under care for OA in the Veterans Affairs (VA) health care system. Comorbidity scores were calculated using 1 year of data from VA inpatient and outpatient databases (Charlson Score, Elixhauser method), as well as pharmacy data (RxRisk-V). Model selection was used to identify the best comorbidity index for predicting 3 health service use variables: number of physician visits, number of prescriptions used, and hospitalization probability. Specifically, Akaike's Information Criterion (AIC) was used to determine the best model for each health service outcome variable. Model fit was also evaluated.The study population comprised 306 patients who were under care for OA in the Veterans Affairs (VA) health care system. Comorbidity scores were calculated using 1 year of data from VA inpatient and outpatient databases (Charlson Score, Elixhauser method), as well as pharmacy data (RxRisk-V). Model selection was used to identify the best comorbidity index for predicting 3 health service use variables: number of physician visits, number of prescriptions used, and hospitalization probability. Specifically, Akaike's Information Criterion (AIC) was used to determine the best model for each health service outcome variable. Model fit was also evaluated.ResultsAll 3 comorbidity indices were significant predictors of each health service outcome (P < 0.01). However, based on AIC values, models using the RxRisk-V and Elixhauser indices as predictor variables were better than models using the Charlson Score. The model using the RxRisk-V index as a predictor was the best for the outcome of prescription medication use, and the model with the Elixhauser index was the best for the outcome of physician visits.All 3 comorbidity indices were significant predictors of each health service outcome (P < 0.01). However, based on AIC values, models using the RxRisk-V and Elixhauser indices as predictor variables were better than models using the Charlson Score. The model using the RxRisk-V index as a predictor was the best for the outcome of prescription medication use, and the model with the Elixhauser index was the best for the outcome of physician visits.ConclusionThe Rx-Risk-V and Elixhauser are suitable comorbidity measures for examining health services use among patients with OA. Both indices are derived from administrative databases and can efficiently capture comorbidity among large patient populations.The Rx-Risk-V and Elixhauser are suitable comorbidity measures for examining health services use among patients with OA. Both indices are derived from administrative databases and can efficiently capture comorbidity among large patient populations.

Examine primary care physicians’ use of counseling techniques when treating overweight and obese patients and the association with mediators of behavior change as well as change in nutrition, exercise, and weight loss attempts.We audio recorded office encounters between 40 physicians and 461 patients. Encounters were coded for physician use of selected counseling techniques using the Motivational Interviewing Treatment Integrity (MITI) scale. Patient motivation and confidence as well as Fat and Fiber Diet score (1–4), Framingham physical activity questionnaire (MET-minutes), and weight loss attempts (yes/no) were assessed by surveys. Generalized linear models were fit, including physician, patient, and visit level covariates.Patients whose physicians were rated higher in empathy improved their Fat and Fiber intake 0.18 units (95% CI 0, 0.4). When physicians used “MI consistent” techniques, patients reported higher confidence to improve nutrition (OR 2.57, 95% CI 1.2, 5.7).When physicians used counseling techniques consistent with MI principles, some of their patients’ weight-related attitudes and behaviors improved.Physicians may not be able to employ formal MI during a clinic visit. However, use of counseling techniques consistent with MI principles, such as expression of empathy, may improve patients’ weight-related attitudes and behaviors.

Characteristics that may influence participation in DNA banks are not well defined. The purpose of this study was to examine characteristics associated with participation in a DNA bank among veterans diagnosed with Amyotrophic Lateral Sclerosis (ALS).Veterans who screened eligible for the National Registry of Veterans with ALS were initially contacted about the DNA Bank via telephone and then mailed a consent form. Registry participants were then categorized as consented for the DNA bank, actively refused, or passively refused (consent form not returned after > 3 months and multiple reminders). The associations of consent status with age, gender, race, military branch, years of military service, VA health system use, and ALS Functional Rating Scale (ALSFRS) scores were examined.Registry participants (N = 1020) were 98% male, 9.5% non-white, and the mean age was 64.1 years. 61.1% of participants were current VA health system users, and the branches of service were: Army (46.1%), Navy (22.1%), Air Force (23.2%), and Marines (8.3%). A total of 14.7% of Registry participants refused DNA banking (9.4% active refusal, 5.3% passive refusal). Results from multivariable models indicated participants who were non-White, VA users, or had lower ALSFRS scores (reflecting poorer function) had higher odds of refusal. Race and VA use were associated with active refusal, while age and ALSFRS score were associated with passive refusal.Although the overall refusal rate for DNA banking was relatively low, we still found important differences in consent by race, VA use, and functional status in this cohort of veterans with ALS. Because differential participation in DNA banking may influence generalizability, further efforts are needed to understand and intervene to reduce these differences.

Background It has been reported in the quantitative trait locus (QTL) literature that when testing for QTL location and effect, the statistical power supporting methodologies based on two markers and their estimated genetic map is higher than for the genetic map independent methodologies known as single marker analyses. Close examination of these reports reveals that the two marker approaches are more powerful than single marker analyses only in certain cases. Simulation studies are a commonly used tool to determine the behavior of test statistics under known conditions. We conducted a simulation study to assess the general behavior of an intersection test and a two marker test under a variety of conditions. The study was designed to reveal whether two marker tests are always more powerful than intersection tests, or whether there are cases when an intersection test may outperform the two marker approach. We present a reanalysis of a data set from a QTL study of ovariole number in Drosophila melanogaster. Results Our simulation study results show that there are situations where the single marker intersection test equals or outperforms the two marker test. The intersection test and the two marker test identify overlapping regions in the reanalysis of the Drosophila melanogaster data. The region identified is consistent with a regression based interval mapping analysis. Conclusion We find that the intersection test is appropriate for analysis of QTL data. This approach has the advantage of simplicity and for certain situations supplies equivalent or more powerful results than a comparable two marker test.

Quantitative trait locus (QTL) mapping methodology for continuous normally distributed traits is the subject of much attention in the literature. Binary trait locus (BTL) mapping in experimental populations has received much less attention. A binary trait by definition has only two possible values, and the penetrance parameter is restricted to values between zero and one. Due to this restriction, the infinitesimal model appears to come into play even when only a few loci are involved, making selection of an appropriate genetic model in BTL mapping challenging. We present a probability model for an arbitrary number of BTL and demonstrate that, given adequate sample sizes, the power for detecting loci is high under a wide range of genetic models, including most epistatic models. A novel model selection strategy based upon the underlying genetic map is employed for choosing the genetic model. We propose selecting the "best" marker from each linkage group, regardless of significance. This reduces the model space so that an efficient search for epistatic loci can be conducted without invoking stepwise model selection. This procedure can identify unlinked epistatic BTL, demonstrated by our simulations and the reanalysis of Oncorhynchus mykiss experimental data.

Objective-Evidence suggests that physicians' use of Motivational Interviewing (MI) techniques helps patients lose weight. We assessed patient, physician, relationship, and systems predictors of length of weight-loss discussions and whether physicians' used MI techniques.

Physicians should counsel overweight adolescents about nutrition and exercise. We audio recorded 30 physician-adolescent encounters. Female, older, normal weight physicians and pediatricians were more Motivational Interviewing adherent. When physicians used MI skills, patients increased exercise, lost weight, and reduced screen time. Physicians should use MI techniques to help adolescents change.

Background:We conducted a 12-month follow-up study on participants in the Dietary Approaches to Stop Hypertension (DASH)-Sodium trial to determine the impact of the DASH diet and 150, 100, or 50 mmol/day of sodium after discontinuation of the feeding intervention.

A potential venue to improve healthcare efficiency is to effectively tailor individualized treatment strategies by
incorporating patient level predictor information such as environmental exposure, biological, and genetic marker measurements.
Many useful statistical methods for deriving individualized treatment rules (ITR) have become available in recent
years. Prior to adopting any ITR in clinical practice, it is crucial to evaluate its value in improving patient outcomes. Existing
methods for quantifying such values mainly consider either a single marker or semi-parametric methods that are subject to
bias under model misspecification. In this article, we consider a general setting with multiple markers and propose a two-step robust method to derive ITRs and evaluate their values. We also propose procedures for comparing different ITRs, which can be used to quantify the incremental value of new markers in improving treatment selection. While working models are used in step I to approximate optimal ITRs, we add a layer of calibration to guard against model misspecification and further assess the value of the ITR non-parametrically, which ensures the validity of the inference. To account for the sampling variability of the estimated rules and their corresponding values, we propose a resampling procedure to provide valid confidence intervals for the value functions as well as for the incremental value of new markers for treatment selection. Our proposals are examined through extensive simulation studies and illustrated with the data from a clinical trial that studies the effects of two drug combinations on HIV-1 infected patients.

Amyloid β (Aβ) peptides, the main pathological species associated with Alzheimer&#x27;s disease (AD), disturb intracellular calcium homeostasis, which in turn activates the calcium-dependent phosphatase calcineurin (CaN). CaN activation induced by Aβ leads to pathological morphological changes in neurons, and overexpression of constitutively active calcineurin is sufficient to generate a similar phenotype, even without Aβ. Here, we tested the hypothesis that calcineurin mediates neurodegenerative effects via activation of the nuclear transcription factor of activated T-cells (NFAT). We found that both spine loss and dendritic branching simplification induced by Aβ exposure were mimicked by constitutively active NFAT, and abolished when NFAT activation was blocked using the genetically encoded inhibitor VIVIT. When VIVIT was specifically addressed to the nucleus, identical beneficial effects were observed, thus enforcing the role of NFAT transcriptional activity in Aβ-related neuroto...

Calcineurin has been implicated as part of a critical signaling pathway for learning and memory, and recent data suggest that calcineurin activation mediates some of the neurotoxicity of the Alzheimer related neurotoxin Aβ. Immunosuppression via calcineurin inhibition with the compound FK506 is an important treatment for organ transplant patients. Here we use Golgi impregnation techniques, along with a new survival analysis-based statistical approach for analysis of dendritic complexity, to show that in healthy adult mice one week of treatment with FK506 affects both the branching patterns and dendritic spine density of cortical neurons. These results indicate that calcineurin inhibition leads to readily detectable changes in brain morphology, further implicating calcineurin related pathways in both the function and structure of the adult brain.