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1.  Serum Inflammatory Markers and Risk of Colorectal Cancer in Patients with Inflammatory Bowel Diseases 
Patients with inflammatory bowel diseases (IBD; Crohn’s disease (CD), ulcerative colitis (UC)) are at increased risk of colorectal cancer (CRC). Persistent inflammation is hypothesized to increase risk of CRC in patients with IBD; however the few studies in this area have been restricted to cross-sectional assessments of histologic severity. No prior studies have examined association between C-reactive protein or erythrocyte sedimentation rate (ESR) elevation and risk of CRC in an IBD cohort.
From a multi-institutional validated IBD cohort, we identified all patients with at least one measured CRP or ESR value. Patients were stratified into quartiles of severity of inflammation based on their median CRP or ESR, and subsequent diagnosis of CRC was ascertained. Logistic regression adjusting for potential confounders was used to identify the independent association between CRP or ESR elevation and risk of CRC.
Our study included 3,145 patients with at least 1 CRP (CRP cohort) and 4,008 with at least 1 ESR (ESR cohort). Thirty-three patients in the CRP cohort and 102 patients in the ESR cohort developed colorectal cancer during a median follow-up of 5 years, at a median age of 55 years. On multivariate analysis, there was a significant increase in risk of CRC across quartiles of CRP elevation (Ptrend 0.017, Odds ratio for Q4 vs. Q1: 2.72, 95% CI 0.95 – 7.76). Similarly higher median ESR was also independently associated with risk of CRC across the quartiles (OR 2.06, 95% CI 1.14 – 3.74) (Ptrend=0.007).
An elevated CRP or ESR is associated with increased risk of CRC in patients with IBD.
PMCID: PMC4085150  PMID: 24407106
Crohn’s disease; ulcerative colitis; C-reactive protein; ESR; colorectal cancer
2.  Recent BRCAPRO upgrades significantly improve calibration 
The recent release of version 2.0-8 of the BayesMendel package contains an updated BRCAPRO risk prediction model, which includes revised modeling of Contralateral Breast Cancer (CBC) penetrance, provisions for pedigrees of mixed ethnicity and an adjustment for mastectomies among family members. We estimated penetrance functions for contralateral breast cancer by a combination of parametric survival modeling of literature data and deconvolution of SEER9 data. We then validated the resulting updated model of CBC in BRCAPRO by comparing it with the previous release (BayesMendel 2.0-7), using pedigrees from the Cancer Genetics Network (CGN) Model Validation Study. Version 2.0-8 of BRCAPRO discriminates BRCA1/BRCA2 carriers from non-carriers with similar accuracy compared to the previous version (increase in AUC: 0.0043), is slightly more precise in terms of RMSE (decrease in RMSE: 0.0108), and it significantly improves calibration (ratio of observed to expected events of 0.9765 in version 2.0-8, compared to 0.8910 in version 2.0-7). We recommend that the new version be used in clinical counseling, particularly in settings where families with CBC are common.
PMCID: PMC4119541  PMID: 24891549
Contralateral Breast cancer; risk assessment; BRCA1; BRCA2; cumulative risk; calibration
3.  [18F]-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography of LAPC4-CR Castration-Resistant Prostate Cancer Xenograft Model in Soft Tissue Compartments1 
Translational Oncology  2015;8(3):147-153.
Preclinical xenograft models have contributed to advancing our understanding of the molecular basis of prostate cancer and to the development of targeted therapy. However, traditional preclinical in vivo techniques using caliper measurements and survival analysis evaluate the macroscopic tumor behavior, whereas tissue sampling disrupts the microenvironment and cannot be used for longitudinal studies in the same animal. Herein, we present an in vivo study of [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) designed to evaluate the metabolism within the microenvironment of LAPC4-CR, a unique murine model of castration-resistant prostate cancer. Mice bearing LAPC4-CR subcutaneous tumors were administered [18F]-FDG via intravenous injection. After a 60-minute distribution phase, the mice were imaged on a PET/CT scanner with submillimeter resolution; and the fused PET/CT images were analyzed to evaluate tumor size, location, and metabolism across the cohort of mice. The xenograft tumors showed [18F]-FDG uptake that was independent of tumor size and was significantly greater than uptake in skeletal muscle and liver in mice (Wilcoxon signed-rank P values of .0002 and .0002, respectively). [18F]-FDG metabolism of the LAPC4-CR tumors was 2.1 ± 0.8 ID/cm3*wt, with tumor to muscle ratio of 7.4 ± 4.7 and tumor to liver background ratio of 6.7 ± 2.3. Noninvasive molecular imaging techniques such as PET/CT can be used to probe the microenvironment of tumors in vivo. This study showed that [18F]-FDG-PET/CT could be used to image and assess glucose metabolism of LAPC4-CR xenografts in vivo. Further work can investigate the use of PET/CT to quantify the metabolic response of LAPC4-CR to novel agents and combination therapies using soft tissue and possibly bone compartment xenograft models.
PMCID: PMC4487789  PMID: 26055171
4.  Association Between Reduced Plasma 25-hydroxy Vitamin D and Increased Risk of Cancer in Patients with Inflammatory Bowel Diseases 
Background & Aims
Vitamin D deficiency is common among patients with inflammatory bowel diseases (IBD) (Crohn’s disease or ulcerative colitis). The effects of low plasma 25-hydroxy vitamin D (25[OH]D) on outcomes other than bone health are understudied in patients with IBD. We examined the association between plasma level of 25(OH)D and risk of cancers in patients with IBD.
From a multi-institutional cohort of patients with IBD, we identified those with at least 1 measurement of plasma 25(OH)D. The primary outcome was development of any cancer. We examined the association between plasma 25(OH)D and risk of specific subtypes of cancer, adjusting for potential confounders in a multivariate regression model.
We analyzed data from 2809 patients with IBD and a median plasma level of 25(OH)D of 26 ng/mL. Nearly one-third had deficient levels of vitamin D (<20 ng/mL). During a median follow-up period of 11 y, 196 patients (7%) developed cancer, excluding non-melanoma skin cancer (41 cases of colorectal cancer). Patients with vitamin D deficiency had an increased risk of cancer (adjusted odds ratio=1.82; 95% CI, 1.25–2.65) compared to those with sufficient levels. Each 1 ng/mL increase in plasma 25(OH)D was associated with an 8% reduction in risk of colorectal cancer (odds ratio=0.92; 95% CI, 0.88–0.96). A weaker inverse association was also identified for lung cancer.
In a study of from 2809 patients with IBD, low plasma level of 25(OH)D was associated with an increased risk of cancer—especially colorectal cancer.
PMCID: PMC3995841  PMID: 24161349
Crohn’s disease; ulcerative colitis; risk factor; colorectal cancer; vitamin D; malignancy
5.  Higher plasma 25(OH)D is associated with reduced risk of Clostridium difficile infection in patients with inflammatory bowel diseases 
Alimentary pharmacology & therapeutics  2014;39(10):1136-1142.
Patients with inflammatory bowel diseases (IBD) have an increased risk of clostridium difficile infection (CDI). Cathelicidins are anti-microbial peptides that attenuate colitis and inhibit the effect of clostridial toxins. Plasma 25(OH)D stimulates production of cathelicidins.
To examine the association between plasma 25(OH)D and CDI in patients with IBD
From a multi-institutional IBD cohort, we identified patients with at least one measured plasma 25(OH)D. Our primary outcome was development of CDI. Multivariate logistic regression models adjusting for potential confounders were used to identify independent effect of plasma 25(OH)D on risk of CDI.
We studied 3,188 IBD patients whom 35 patients developed CDI. Patients with CDI-IBD were older and had greater co-morbidity. The mean plasma 25(OH)D level was significantly lower in patients who developed CDI (20.4ng/ml) compared to non-CDI IBD patients (27.1ng/mL) (p=0.002). On multivariate analysis, each 1ng/ml increase in plasma 25(OH)D was associated with a 4% reduction in risk of CDI (OR 0.96, 95% CI 0.93 – 0.99, p = 0.046). Compared t o individuals with vitamin D > 20ng/mL, patients with levels < 20ng/mL were more likely to develop CDI (OR 2.27, 95% CI 1.16 – 4.44). The mean plasma 25(OH)D in patients with CDI who subsequently died was significantly lower (12.8+8.1ng/ml) compared to those who were alive at the end of follow-up (24.3+13.2ng/ml) (p=0.01).
Higher plasma 25(OH)D is associated with reduced risk of C difficile infection in patients with IBD. Further studies of therapeutic supplementation of vitamin D in IBD-CDI patients may be warranted.
PMCID: PMC4187206  PMID: 24641590
Crohn’s disease; ulcerative colitis; Clostridium difficile; vitamin D
6.  SQSTM1 is a Pathogenic Target of 5q Copy Number Gains in Kidney Cancer 
Cancer cell  2013;24(6):738-750.
Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer and is often linked to loss of chromosome 3p, which harbors the VHL tumor suppressor gene, loss of chromosome 14q, which includes HIF1A, and gain of chromosome 5q. The relevant target(s) on chromosome 5q is not known. Here we show that 5q amplification leads to overexpression of the SQSTM1 oncogene in ccRCC lines and tumors. Overexpression of SQSTM1 in ccRCC lines promoted resistance to redox stress and increased soft agar growth while downregulation of SQSTM1 decreased resistance to redox stress, impaired cellular fitness, and decreased tumor formation. Therefore the selection pressure to amplify 5q in ccRCC is driven, at least partly, by SQSTM1.
PMCID: PMC3910168  PMID: 24332042
7.  Normalization of Plasma 25-hydroxy Vitamin D is Associated with Reduced Risk of Surgery in Crohn’s Disease 
Inflammatory bowel diseases  2013;19(9):1921-1927.
Vitamin D may have an immunological role in Crohn’s disease (CD) and ulcerative colitis (UC). Retrospective studies suggested a weak association between vitamin D status and disease activity but have significant limitations.
Using a multi-institution inflammatory bowel disease (IBD) cohort, we identified all CD and UC patients who had at least one measured plasma 25-hydroxy vitamin D [25(OH)D]. Plasma 25(OH)D was considered sufficient at levels ≥ 30ng/mL. Logistic regression models adjusting for potential confounders were used to identify impact of measured plasma 25(OH)D on subsequent risk of IBD-related surgery or hospitalization. In a subset of patients where multiple measures of 25(OH)D were available, we examined impact of normalization of vitamin D status on study outcomes.
Our study included 3,217 patients (55% CD, mean age 49 yrs). The median lowest plasma 25(OH)D was 26ng/ml (IQR 17–35ng/ml). In CD, on multivariable analysis, plasma 25(OH)D < 20ng/ml was associated with an increased risk of surgery (OR 1.76 (1.24 – 2.51) and IBD-related hospitalization (OR 2.07, 95% CI 1.59 – 2.68) compared to those with 25(OH)D ≥ 30ng/ml. Similar estimates were also seen for UC. Furthermore, CD patients who had initial levels < 30ng/ml but subsequently normalized their 25(OH)D had a reduced likelihood of surgery (OR 0.56, 95% CI 0.32 – 0.98) compared to those who remained deficient.
Low plasma 25(OH)D is associated with increased risk of surgery and hospitalizations in both CD and UC and normalization of 25(OH)D status is associated with a reduction in the risk of CD-related surgery.
PMCID: PMC3720838  PMID: 23751398
Crohn’s disease; ulcerative colitis; vitamin D; surgery; hospitalization
8.  Improving Case Definition of Crohn’s Disease and Ulcerative Colitis in Electronic Medical Records Using Natural Language Processing: A Novel Informatics Approach 
Inflammatory bowel diseases  2013;19(7):1411-1420.
Prior studies identifying patients with inflammatory bowel disease (IBD) utilizing administrative codes have yielded inconsistent results. Our objective was to develop a robust electronic medical record (EMR) based model for classification of IBD leveraging the combination of codified data and information from clinical text notes using natural language processing (NLP).
Using the EMR of 2 large academic centers, we created data marts for Crohn’s disease (CD) and ulcerative colitis (UC) comprising patients with ≥ 1 ICD-9 code for each disease. We utilized codified (i.e. ICD9 codes, electronic prescriptions) and narrative data from clinical notes to develop our classification model. Model development and validation was performed in a training set of 600 randomly selected patients for each disease with medical record review as the gold standard. Logistic regression with the adaptive LASSO penalty was used to select informative variables.
We confirmed 399 (67%) CD cases in the CD training set and 378 (63%) UC cases in the UC training set. For both, a combined model including narrative and codified data had better accuracy (area under the curve (AUC) for CD 0.95; UC 0.94) than models utilizing only disease ICD-9 codes (AUC 0.89 for CD; 0.86 for UC). Addition of NLP narrative terms to our final model resulted in classification of 6–12% more subjects with the same accuracy.
Inclusion of narrative concepts identified using NLP improves the accuracy of EMR case-definition for CD and UC while simultaneously identifying more subjects compared to models using codified data alone.
PMCID: PMC3665760  PMID: 23567779
Crohn’s disease; ulcerative colitis; disease cohort; natural language processing; informatics
9.  Similar risk of Depression and Anxiety following surgery or hospitalization for Crohn’s disease and Ulcerative colitis 
Psychiatric co-morbidity is common in Crohn’s disease (CD) and ulcerative colitis (UC). IBD-related surgery or hospitalizations represent major events in the natural history of disease. Whether there is a difference in risk of psychiatric co-morbidity following surgery in CD and UC has not been examined previously.
We used a multi-institution cohort of IBD patients without a diagnosis code for anxiety or depression preceding their IBD-related surgery or hospitalization. Demographic, disease, and treatment related variables were retrieved. Multivariate logistic regression analysis was performed to individually identify risk factors for depression and anxiety.
Our study included a total of 707 CD and 530 UC patients who underwent bowel resection surgery and did not have depression prior to surgery. The risk of depression 5 years after surgery was 16% and 11% in CD and UC respectively. We found no difference in the risk of depression following surgery in CD and UC patients (adjusted OR 1.11, 95%CI 0.84 – 1.47). Female gender, co-morbidity, immunosuppressant use, perianal disease, stoma surgery, and early surgery within 3 years of care predicted depression after CD-surgery; only female gender and co-morbidity predicted depression in UC. Only 12% of the CD cohort had ≥ 4 risk factors for depression, but among them nearly 44% were subsequently received a diagnosis code for depression.
IBD-related surgery or hospitalization is associated with a significant risk for depression and anxiety with a similar magnitude of risk in both diseases.
PMCID: PMC3627544  PMID: 23337479
Crohn’s disease; depression; anxiety; surgery; hospitalization
10.  Psychiatric co-morbidity is Associated with Increased risk of Surgery in Crohn’s disease 
Psychiatric co-morbidity, in particular major depression and anxiety is common in patients with Crohn’s disease (CD) and ulcerative colitis (UC). Prior studies examining this may be confounded by the co-existence of functional bowel symptoms. Limited data exists examining an association between depression or anxiety and disease-specific endpoints such as bowel surgery.
Using a multi-institution cohort of patients with CD and UC, we identified those who also had co-existing psychiatric co-morbidity (major depressive disorder or generalized anxiety). After excluding those diagnosed with such co-morbidity for the first time following surgery, we used multivariate logistic regression to examine the independent effect of psychiatric co-morbidity on IBD-related surgery and hospitalization. To account for confounding by disease severity, we adjusted for a propensity score estimating likelihood of psychiatric co-morbidity influenced by severity of disease in our models.
A total of 5,405 CD and 5,429 UC patients were included in this study; one-fifth had either major depressive disorder or generalized anxiety. In multivariate analysis, adjusting for potential confounders and the propensity score, presence of mood or anxiety co-morbidity was associated with a 28% increase in risk of surgery in CD (OR 1.28, 95% CI 1.03 – 1.57) but not UC (OR 1.01, 95% CI 0.80 – 1.28). Psychiatric co-morbidity was associated with increased healthcare utilization.
Depressive disorder or generalized anxiety is associated with a modestly increased risk of surgery in patients with CD. Interventions addressing this may improve patient outcomes.
PMCID: PMC3552092  PMID: 23289600
Crohn’s disease; ulcerative colitis; depression; surgery; hospitalization
11.  The penetrance of ductal carcinoma in situ among BRCA1 and BRCA2 mutation carriers 
Breast cancer research and treatment  2012;137(1):10.1007/s10549-012-2345-5.
Ductal carcinoma in situ (DCIS) is a precancerous lesion of the female breast and is strongly suspected to be a precursor of invasive breast cancer (IBC). Our goal is the estimation of the age-specific and lifetime penetrances of DCIS among carriers of either a BRCA1 or BRCA2 deleterious mutation. We jointly re-analyze the SEER9 database and a previous study by Claus et al. (JAMA 293:964–969, 2005). Estimation is performed via Bayes theorem after the evaluation of the ratio of age-specific DCIS incidences, and extrapolation to the general population of the study-specific penetrance obtained from Claus et al. From the SEER9 database, we estimate the lifetime risk of DCIS to be 0.98 %, in contrast to value of 12.5 % usually reported for IBC. By extending the result in Claus et al. to the general population, we obtain a lifetime risk for carriers of a deleterious mutation of either BRCA1 or BRCA2 of 6.21 % (95 % CI 6.09–6.33 %). The increase in lifetime risk of DCIS for a BRCA mutation carrier compared to a non-carrier is therefore about six-fold. Our quantification is directly relevant to the identification and genetic counseling of BRCA mutation carriers, and emphasizes the potential importance of including information on diagnoses of DCIS in counseling of individuals who are at familial risk for breast cancer. All these factors can contribute to a more specific and targeted prevention, potentially reducing the impact of IBC among BRCA mutation carriers.
PMCID: PMC3836600  PMID: 23184082
Ductal carcinoma in situ; Penetrance function; BRCA1; BRCA2; Mutation carrier; Age-specific risk; Lifetime risk
12.  Orthotopic xenografts of RCC retain histological, immunophenotypic and genetic features of tumors in patients 
The Journal of pathology  2011;225(2):212-221.
Renal cell carcinoma (RCC) is an aggressive malignancy with limited responsiveness to existing treatments. In vivo models of human cancer, including RCC, are critical for developing more effective therapies. Unfortunately, current RCC models do not accurately represent relevant properties of the human disease.
The goal of this study was to develop clinically relevant animal models of RCC for preclinical investigations. We transplanted intact human tumor tissue fragments orthotopically in immunodeficient mice. The xenografts were validated by comparing the morphologic, phenotypic, and genetic characteristics of the kidney tumor tissues before and after implantation.
Twenty kidney tumors were transplanted into mice. Successful tumor growth was detected in 19 cases (95%). The histopathologic and immunophenotypic features of the xenografts and those of the original tumors largely overlapped in all the cases. Evaluation of genetic alterations in a subset of 10 cases demonstrated that the grafts largely retained the genetic features of the pre-implantation RCC tissues. Indeed, primary tumors and corresponding grafts displayed identical VHL mutations. Moreover, an identical pattern of DNA copy amplification or loss was observed in 6 of 10 cases (60%).
In summary, orthotopic engrafting of RCC tissue fragments can be successfully used to generate animal models that closely resemble RCC in patients. These models will be invaluable for in vivo preclinical drug testing, and for deeper understanding of kidney carcinogenesis.
PMCID: PMC3793840  PMID: 21710693
Renal Cell Carcinoma; mouse model; orthotopic xenograft; sub-renal capsule implantation
13.  Trends and Outcomes Associated With Serum Albumin Concentration Among Incident Dialysis Patients in the United States 
Objective and Methods:
Serum albumin concentrations are associated with mortality, and respond to nutritional and inflammatory states. To explore whether changing demographics and practice patterns in dialysis have influenced serum albumin concentrations, we analyzed trends in serum albumin among incident patients on dialysis from 1995 through 2004.
Mean serum albumin concentrations declined significantly over time, even after accounting for changes in age, diabetes, body size, and other factors. Although laboratory assays were not uniform within or across years, serum albumin declined over time, regardless of the reported laboratory lower limit of normal. Moreover, serum albumin retained its potent association with mortality over time. Lower serum albumin was especially hazardous among younger patients and blacks, and was less hazardous among persons with diabetes as a primary cause of kidney disease.
Despite higher body weights and the initiation of dialysis earlier in the course of progressive chronic kidney disease, hypoalbuminemia remains common and hazardous to persons starting dialysis.
PMCID: PMC3786208  PMID: 18558296
14.  Landmark Prediction of Long Term Survival Incorporating Short Term Event Time Information 
In recent years, a wide range of markers have become available as potential tools to predict risk or progression of disease. In addition to such biological and genetic markers, short term outcome information may be useful in predicting long term disease outcomes. When such information is available, it would be desirable to combine this along with predictive markers to improve the prediction of long term survival. Most existing methods for incorporating censored short term event information in predicting long term survival focus on modeling the disease process and are derived under restrictive parametric models in a multi-state survival setting. When such model assumptions fail to hold, the resulting prediction of long term outcomes may be invalid or inaccurate. When there is only a single discrete baseline covariate, a fully non-parametric estimation procedure to incorporate short term event time information has been previously proposed. However, such an approach is not feasible for settings with one or more continuous covariates due to the curse of dimensionality. In this paper, we propose to incorporate short term event time information along with multiple covariates collected up to a landmark point via a flexible varying-coefficient model. To evaluate and compare the prediction performance of the resulting landmark prediction rule, we use robust non-parametric procedures which do not require the correct specification of the proposed varying coefficient model. Simulation studies suggest that the proposed procedures perform well in finite samples. We illustrate them here using a dataset of post-dialysis patients with end-stage renal disease.
PMCID: PMC3535339  PMID: 23293405
Landmark Prediction; Risk Prediction; Survival Time; Varying Coefficient Model
15.  Evaluation of Patient-Reported Quality-of-Life Outcomes After Renal Surgery 
Urology  2012;79(6):1268-1273.
To assess the feasibility of two patient-reported health related quality of life (HRQOL) instruments, CARE and SF-12, as tools for evaluating HRQOL outcome consequences following renal surgery, and to determine which domains of these HRQOL instruments are most sensitive to HRQOL outcome effects of renal surgery.
Patients completed CARE and SF-12 preoperatively (baseline) and at 2, 4, 12 and 24 weeks after surgery. Clinical data, patient response rate, HRQOL changes over time, and likelihood of patient return to baseline HRQOL were evaluated.
Seventy-one patients were enrolled. Sixty patients completed the baseline and at least one follow-up set of questionnaires. The CARE pain, gastrointestinal (GI) and activity domain scores and the SF-12 physical composite score (PCS) were sensitive to changes in HRQOL (all p<0.05), whereas other domain subscores of these instruments did not change from pre-surgical baseline to post-surgical follow-up. Postsurgical HRQOL effects detected by the CARE pain, GI, and activity domains, and SF-12 PCS were most evident at 2 weeks (all p<0.001). The CARE composite score demonstrated 74% and 50% of patients returned to within 90% of baseline 4 weeks after radical and partial nephrectomy respectively.
Evaluation of patient-reported HRQOL outcomes after renal surgery is feasible, our findings suggest that the activity, pain, and GI domains of CARE and PCS subscore of the SF-12 are sensitive measures of HRQOL outcome consequences of renal surgery and represent appropriate measures of either care quality or comparative effectiveness analyses of robotic, laparoscopic, and open renal surgery.
PMCID: PMC3367127  PMID: 22542421
renal cell carcinoma; nephrectomy; quality of life; outcomes
16.  Developing functional workspace for the movement of trunk circumduction in healthy young subjects: a reliability study 
The lumbar range of motion has traditionally been used to assess disability in patients with low back disorders. Controversy exists about how movement ranges in static positions or in a single straight plane is related to the functional status of the patients. The trunk circumduction, as the result of neuromuscular coordination, is the integrated movements from three dimensions. The functional workspace stands for the volume of movement configuration from the trunk circumduction and represents all possible positions in three dimensions. By using single quantitative value, the functional workspace substitutes the complicated joint linear or angular motions. The aim of this study is to develop the functional workspace of the trunk circumduction (FWTC) considering possible functional positions in three dimensional planes. The reliability of the trunk circumduction is examined.
Test-retest reliability was performed with 18 healthy young subjects. A three-dimensional (3-D) Motion Analysis System was used to record the trunk circumduction. The FWTC was defined and calculated based on the volume of the cone that was formed as the resultant scanned area of markers, multiplied by the length of the body segment. The statistical analysis of correlation was performed to describe the relation of maximal displacements of trunk circumduction and straight planes: sagittal and coronal.
The results of this study indicate that the movement of trunk circumduction measured by motion analysis instruments is a reliable tool. The ICC value is 0.90-0.96, and the means and standard deviations of the normalized workspace are: C7 0.425 (0.1162); L1 0.843 (0.2965); and knee 0.014 (0.0106). Little correlations between the maximal displacement of trunk circumduction and that of straight planes are shown and therefore suggest different movement patterns exist.
This study demonstrates high statistical reliability for the FWTC, which is important for the potential development as the functional assessment technique. The FWTC provides a single integrated value to represent angular and linear measurements of different joints and planes. Future study is expected to carry out the FWTC to evaluate the amount of workspace for the functional status of patients with low back injuries or patients with spinal surgery.
PMCID: PMC3598346  PMID: 23311750
Trunk circumduction; Motion analysis; Functional workspace
17.  Diaphragm Used with Replens Gel and Risk of Bacterial Vaginosis: Results from a Randomized Controlled Trial 
Background. Bacterial vaginosis (BV) has been linked to female HIV acquisition and transmission. We investigated the effect of providing a latex diaphragm with Replens and condoms compared to condom only on BV prevalence among participants enrolled in an HIV prevention trial. Methods. We enrolled HIV-seronegative women and obtained a vaginal swab for diagnosis of BV using Nugent's criteria; women with BV (score 7–10) were compared to those with intermediate (score 4–6) and normal flora (score 0–3). During quarterly follow-up visits over 12–24 months a vaginal Gram stain was obtained. The primary outcome was serial point prevalence of BV during followup. Results. 528 participants were enrolled; 213 (40%) had BV at enrollment. Overall, BV prevalence declined after enrollment in women with BV at baseline (OR = 0.4, 95% CI 0.29–.56) but did not differ by intervention group. In the intention-to-treat analysis BV prevalence did not differ between the intervention and control groups for women who had BV (OR = 1.01, 95% CI 0.52–1.94) or for those who did not have BV (OR = 1.21, 95% CI 0.65–2.27) at enrollment. Only 2.1% of participants were treated for symptomatic BV and few women (5–16%) were reported using anything else but water to cleanse the vagina over the course of the trial. Conclusions. Provision of the diaphragm, Replens, and condoms did not change the risk of BV in comparison to the provision of condoms alone.
PMCID: PMC3485870  PMID: 23133307
18.  Incorporating short-term outcome information to predict long-term survival with discrete markers 
In disease screening and prognosis studies, an important task is to determine useful markers for identifying high-risk subgroups. Once such markers are established, they can be incorporated into public health practice to provide appropriate strategies for treatment or disease monitoring based on each individual’s predicted risk. In the recent years, genetic and biological markers have been examined extensively for their potential to signal progression or risk of disease. In addition to these markers, it has often been argued that short-term outcomes may be helpful in making a better prediction of disease outcomes in clinical practice. In this paper we propose model-free non-parametric procedures to incorporate short-term event information to improve the prediction of a long-term terminal event. We include the optional availability of a single discrete marker measurement and assess the additional information gained by including the short-term outcome. We focus on the semi-competing risk setting where the short-term event is an intermediate event that may be censored by the terminal event while the terminal event is only subject to administrative censoring. Simulation studies suggest that the proposed procedures perform well in finite samples. Our procedures are illustrated using a data set of post-dialysis patients with end-stage renal disease.
PMCID: PMC3472667  PMID: 21337601
Biomarkers; Disease prognosis; Risk prediction; Survival analysis
19.  Estimating Regression Parameters in an Extended Proportional Odds Model 
The proportional odds model may serve as a useful alternative to the Cox proportional hazards model to study association between covariates and their survival functions in medical studies. In this article, we study an extended proportional odds model that incorporates the so-called “external” time-varying covariates. In the extended model, regression parameters have a direct interpretation of comparing survival functions, without specifying the baseline survival odds function. Semiparametric and maximum likelihood estimation procedures are proposed to estimate the extended model. Our methods are demonstrated by Monte-Carlo simulations, and applied to a landmark randomized clinical trial of a short course Nevirapine (NVP) for mother-to-child transmission (MTCT) of human immunodeficiency virus type-1 (HIV-1). Additional application includes analysis of the well-known Veterans Administration (VA) Lung Cancer Trial.
PMCID: PMC3420072  PMID: 22904583
Counting process; Estimating function; HIV/AIDS; Maximum likelihood estimation; Semiparametric model; Time-varying covariate
20.  Infection-Related Hospitalizations in Older Patients With End-Stage Renal Disease 
Infection is an important cause of hospitalization and death in patients receiving dialysis. Few studies have examined the full range of infections experienced by dialysis patients. The purpose of this study was to examine the types, rates and risk factors for infection among older persons starting dialysis.
Study Design
Retrospective observational cohort study.
Setting and Participants
The cohort was assembled from the United States Renal Data System and included patients aged 65 to 100 years who initiated dialysis between 1/1/00 and 12/31/02. Exclusions included prior kidney transplant, unknown dialysis modality, or death, loss to follow-up, or transplant during the first 90 days of dialysis. Patients were followed until death, transplant, or study end 12/31/04.
Baseline demographics, co-morbidities, serum albumin and hemoglobin.
Outcomes and Measurements
Infection-related hospitalizations were ascertained using discharge ICD-9-CM codes. Hospitalization rates were calculated for each type of infection. The Wei-Lin-Weissfeld Model was used to examine risk factors for up to 4 infection-related events.
119,858 patients were included, 7,401 of whom were on peritoneal dialysis. During a median follow-up of 1.9 years, infection-related diagnoses were observed in approximately 35% of all hospitalizations. Approximately 50% of patients had at least one infection-related hospitalization. Rates (per 100 person-years) of pulmonary, soft tissue, and genitourinary infections ranged from 8.3 to 10.3 in patients on peritoneal dialysis and 10.2 to 15.3 in patients on hemodialysis. Risk factors for infection included older age, female sex, diabetes, heart failure, pulmonary disease, and low serum albumin.
Use of ICD-9-CM codes, reliance on Medicare claims to capture hospitalizations, use of the Medical Evidence Form to ascertain co-morbidities, absence of data on dialysis access.
Infection-related hospitalization is frequent in older patients on dialysis. A broad range of infections – many unrelated to dialysis access – result in hospitalization in this population.
PMCID: PMC2926212  PMID: 20619518
Dialysis; Infection; Epidemiology; Kidney Failure
21.  Interobserver Variability in the Assessment of CT Imaging Features of Traumatic Brain Injury 
Journal of Neurotrauma  2010;27(2):325-330.
The goal of our study was to determine the interobserver variability between observers with different backgrounds and experience when interpreting computed tomography (CT) imaging features of traumatic brain injury (TBI). We retrospectively identified a consecutive series of 50 adult patients admitted at our institution with a suspicion of TBI, and displaying a Glasgow Coma Scale score ≤12. Noncontrast CT (NCT) studies were anonymized and sent to five reviewers with different backgrounds and levels of experience, who independently reviewed each NCT scan. Each reviewer assessed multiple CT imaging features of TBI and assigned every NCT scan a Marshall and a Rotterdam grading score. The interobserver agreement and coefficient of variation were calculated for individual CT imaging features of TBI as well as for the two scores. Our results indicated that the imaging review by both neuroradiologists and neurosurgeons were consistent with each other. The kappa coefficient of agreement for all CT characteristics showed no significant difference in interpretation between the neurosurgeons and neuroradiologists. The average Bland and Altman coefficients of variation for the Marshall and Rotterdam classification systems were 12.7% and 21.9%, respectively, which indicates acceptable agreement among all five reviewers. In conclusion, there is good interobserver reproducibility between neuroradiologists and neurosurgeons in the interpretation of CT imaging features of TBI and calculation of Marshall and Rotterdam scores.
PMCID: PMC2834438  PMID: 19895192
accuracy; computed tomography; imaging scores; interobserver agreement; traumatic brain injury
22.  Factors Influencing Survival After Relapse From Acute Lymphoblastic Leukemia: A Children's Oncology Group Study 
Despite great progress in curing childhood acute lymphoblastic leukemia, survival after relapse remains poor. We analyzed survival following relapse among 9,585 pediatric patients enrolled on Children's Oncology Group clinical trials between 1988-2002. A total of 1961 patients (20.5%) experienced relapse at any site. The primary endpoint was survival. Patients were subcategorized by site of relapse and timing of relapse from initial diagnosis. Time to relapse remains the strongest predictor of survival. Patients experiencing early relapse less than 18 months from initial diagnosis had a particularly poor outcome with a 5-year survival estimate of 21.0±1.8%. Standard risk patients who relapsed had improved survival compared to their higher risk counterparts; differences in survival for the two risk groups was most pronounced for patients relapsing after 18 months. Adjusting for both time and relapse site, multivariate analysis showed that age (10+ yrs) and presence of CNS disease at diagnosis, male gender, and T-cell disease were significant predictors of inferior post-relapse survival. Of note, there was no difference in survival rates for relapsed patients in earlier versus later era trials. New therapeutic strategies are urgently needed for children with relapsed ALL and efforts should focus on discovering the biological pathways that mediate drug resistance.
PMCID: PMC2872117  PMID: 18818707
relapsed acute lymphoblastic leukemia; Children's Oncology Group; pediatric
Adherence to inhaled anti-inflammatory therapy and self-management skills are essential parts of the asthma treatment plan to improve asthma control and prevent exacerbations. Whether self-management education improves long-term medication adherence is less clear.
A 24-week prospective, randomized controlled trial was performed to study the impact of self-management education on long-term adherence to inhaled corticosteroid (ICS) therapy and markers of asthma control.
After stabilization on ICS medication during a run-in phase, 95 adults with moderate to severe asthma were recruited from a large metropolitan community and 84 were randomized to individualized self-management education including self-monitoring of symptoms and peak flow or usual care with self-monitoring alone. The key components of the 30-minute intervention were asthma information, assessment and correction of inhaler technique, an individualized action plan based on self-monitoring data, and environmental control strategies for relevant allergen and irritant exposures. The intervention was personalized based on pulmonary function, allergen skin test reactivity, and inhaler technique and reinforced at 2 week intervals.
Participants randomized to the self-management intervention maintained consistently higher ICS adherence levels and showed a nine-fold greater odds of more than 60% adherence to prescribed dose compared to controls at the end of the intervention (p=.02) and maintained a three-fold greater odds of higher than 60% adherence at the end of the study. Perceived control of asthma improved (p=.006), nighttime awakenings decreased (p=.03), and inhaled beta-agonist use decreased (p=.01) in intervention participants compared to controls.
Our results show that individualized asthma self-management education attenuates the usual decline in medication adherence and improves clinical markers of asthma control.
PMCID: PMC2729175  PMID: 19348923
Asthma; Self-Management; Adherence; Asthma Control
24.  Accuracy and Anatomical Coverage of Perfusion CT Assessment of the Blood-Brain Barrier Permeability: One Bolus versus Two Boluses 
To assess whether blood-brain barrier permeability (BBBP) values, extracted with the Patlak model from the second perfusion CT (PCT) contrast bolus, are significantly lower than the values extracted from the first bolus in the same patient. Materials and Methods: 125 consecutive patients (29 with acute hemispheric stroke and 96 without stroke) who underwent a PCT study using a prolonged acquisition time up to 3 min were retrospectively identified. The Patlak model was applied to calculate the rate of contrast leakage out of the vascular compartment. Patlak plots were created from the arterial and parenchymal time enhancement curves obtained in multiple regions of interest drawn in ischemic brain tissue and in nonischemic brain tissue. The slope of a regression line fit to the Patlak plot was used as an indicator of BBBP. Square roots of the mean squared errors and correlation coefficients were used to describe the quality of the linear regression model. This was performed separately for the first and the second PCT bolus. Results from the first and the second bolus were compared in terms of BBBP values and the quality of the linear model fitted to the Patlak plot, using generalized estimating equations with robust variance estimation.
BBBP values from the second bolus were not lower than BBBP values from the first bolus in either nonischemic brain tissue [estimated mean with 95% confidence interval: 1.42 (1.10–1.82) ml·100 g−1·min−1 for the first bolus versus 1.64 (1.31–2.05) ml·100 g−1·min−1 for the second bolus, p = 1.00] or in ischemic tissue [1.04 (0.97–1.12) ml·100 g−1·min−1 for the first bolus versus 1.19 (1.11–1.28) ml·100 g−1·min−1 for the second bolus, p = 0.79]. Compared to regression models from the first bolus, the Patlak regression models obtained from the second bolus were of similar or slightly better quality. This was true both in nonischemic and ischemic brain tissue.
The contrast material from the first bolus of contrast for PCT does not negatively influence measurements of BBBP values from the second bolus. The second bolus can thus be used to increase anatomical coverage of BBBP assessment using PCT.
PMCID: PMC2914360  PMID: 18946215
Perfusion computed tomography; Blood-brain barrier permeability; Patlak model

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