Search

Measurements are generally collected as unilateral or bilateral data in clinical trials or observational studies. For example, in ophthalmologic studies, statistical tests are often based on one or two eyes of an individual. For the bilateral data, recent literatures have shown some test procedures that take into account the intraclass correlation between paired organs of the same person. Ma et al. investigated three test procedures under Rosner's model. In this paper, we extend Ma's work for bilateral data to combined bilateral and unilateral data. The proposed procedures are based on the likelihood estimate algorithm derived from the root of 4th order polynomial equations and the Fisher scoring iterations. Simulation studies are performed to compare the testing procedures under different parameter configurations. The result shows that score test has satisfactory type I error rates and powers. Therefore, we recommend score test for testing the homogeneity of proportions. We illustrate the application of the proposed methods with two real world examples.

Bilateral correlated data frequently arise in medical clinical studies such as otolaryngology and ophthalmology. Based on an equal correlation coefficient model, this paper mainly aimed to investigate the statistical inference for the odds ratio of two proportions in bilateral correlated data, including not only three test procedures but also four confidence interval (CI) constructions. Through iterative algorithms, all unknown parameters are estimated in order to construct the likelihood ratio, score and Wald-type tests. Furthermore, the profile likelihood CI, score CI, and Wald-type CI are obtained by the bisection root-finding algorithm. We provided another Wald-type CI based on an asymptotic normality property. The performance of the proposed tests were investigated with regard to empirical type I error rate and power, and CI methods were compared in terms of mean coverage probability and mean interval width. Numerical simulations show that the score test is more robust, and has higher power than other tests. The score CI also has a shorter interval width, and its coverage probability is closer to 0.95. A real example is used to illustrate the proposed methods.

In some medical researches such as ophthalmological, orthopaedic and otolaryngologic studies, it is often of interest to compare multiple groups with a control using data collected from paired organs of patients. The major difficulty in performing the data analysis is to adjust the multiplicity between the comparison of multiple groups, and the correlation within the same patient's paired organs. In this article, we construct asymptotic simultaneous confidence intervals (SCIs) for many-to-one comparisons of proportion differences adjusting for multiplicity and the correlation. The coverage probabilities and widths of the proposed CIs are evaluated by Monte Carlo simulation studies. The methods are illustrated by a real data example.

Medical clinical studies about paired body parts often involve stratified bilateral data. The correlation between responses from paired parts should be taken into account to avoid biased or misleading results. This paper aims to test if the relative risk ratios across strata are equal under the optimal algorithms. Based on different algorithms, we obtain the desired global and constrained maximum likelihood estimations (MLEs). Three asymptotic test statistics (i.e. [Image: see text] , [Image: see text] and [Image: see text] ) are proposed. Monte Carlo simulations are conducted to evaluate the performance of these algorithms with respect to mean square errors of MLEs and convergence rate. The empirical results show Fisher scoring algorithm is usually better than other methods since it has effective convergence rate for global MLEs, and makes mean-square error lower for constrained MLEs. Three test statistics are compared in terms of type I error rate (TIE) and power. Among these statistics, [Image: see text] is recommended according to its robust TIEs and satisfactory power.

Confidence interval (CI) methods for the ratio of two proportions in the presence of correlated bilateral binary data are constructed for comparative clinical trials with stratified design. Simulations are conducted to evaluate the performance of the presented CIs with respect to mean coverage probability (MCP), mean interval width (MIW), and the ratio of mesial non-coverage probability to the distal non-coverage probability (RMNCP). Based on the empirical results, we suggest the use of the proposed CI method based on the complete score statistics (CS) for general applications. An example from a rheumatology study is used to demonstrate the proposed methodologies.

In a parallel group study comparing a new treatment with a standard of care, missing data often occur for various reasons. When the outcome is binary, the data from such studies can be summarized into a 2 × 3 contingency table, with the missing observations in the last column. When the missingness is neither related to the outcome of interest nor related to other outcomes from the study but it is covariate dependent with the sole covariate being treatment, this type of missing data mechanism is considered as missing at random. In 2016, Tian et al. proposed three statistics to test the hypothesis that the response rate is equivalent for a parallel group study with missing data. The asymptotic limiting distributions of these test statistics were used for statistical inference. However, asymptotic approaches for testing proportions generally do not have satisfactory performance with regard to type I error rate control for a clinical trial with the sample size from small to medium. For this reason, we consider an exact approach based on maximization to provide valid and efficient statistical inference for a parallel group study with missing data. Exact approaches can guarantee the type I error rate and they are computationally feasible in this setting. We conduct extensive numerical studies to compare the performance of the exact approach based on the three statistics for a one-sided hypothesis testing problem. We conclude that the exact approach based on the likelihood ratio statistic is more powerful than the exact approach based on the other two statistics. Two real clinical trial data sets are used to illustrate the application of the proposed exact approach.

In ophthalmologic or otolaryngologic studies, bilateral correlated data often arise when observations involving paired organs (e.g., eyes, ears) are measured from each subject. Based on Donner's model , in this paper, we focus on investigating the relationship between the disease probability and covariates (such as ages, weights, gender, and so on) via the logistic regression for the analysis of bilateral correlated data. We first propose a new minorization-maximization (MM) algorithm and a fast quadratic lower bound (QLB) algorithm to calculate the maximum likelihood estimates of the vector of regression coefficients, and then develop three large-sample tests (i.e., the likelihood ratio test, Wald test, and score test) to test if covariates have a significant impact on the disease probability. Simulation studies are conducted to evaluate the performance of the proposed fast QLB algorithm and three testing methods. A real ophthalmologic data set in Iran is used to illustrate the proposed methods.

The most common adverse drug reaction from statins are statin-associated muscle symptoms (SAMS), characterized by myopathy (weakness), myalgia (muscle pain), and commonly elevation in serum creatine kinase. All statins are substrates of the organic anion transporter 1B1 (OATP1B1; gene: SLCO1B1), albeit to different degrees. A genetic polymorphism in SLCO1B1, c.521T>C (rs4149056), markedly decreases OATP1B1 function. The literature is currently unclear as to whether SLCO1B1 c.521T>C is significantly associated with discontinuation of atorvastatin specifically due to SAMS. Our hypothesis was that individuals carrying the SLCO1B1 decreased function 521C allele are more likely to discontinue atorvastatin due to SAMS. This was a retrospective analysis of survey data from 379 Caucasians genotyped for rs4149056 and treated with atorvastatin for at least 12 months. Crude and multivariable logistic regression, adjusted for established risk factors for SAMS, determined the association of SLCO1B1 c.521T>C with discontinuation of atorvastatin due to SAMS (SLCO1B1 521T-homozygotes vs. 521C-carriers). The sample was 51% male, with a mean age of 57 years (SD = 11). Sixty-one percent of participants reported discontinuing atorvastatin due to SAMS, and 32% overall carried the 521C allele. SLCO1B1 521C-carrier status was not a significant predictor of atorvastatin discontinuation in any model: crude OR = 1.07; 95% CI, 0.68-1.66; P = 0.78 and adjusted OR = 1.07; 95% CI, 0.68-1.69; P = 0.76. The results were similar in a sub-group of participants treated with higher doses of atorvastatin (>20 mg). In summary, SLCO1B1 c.521T>C was not significantly associated with discontinuation of atorvastatin therapy due to SAMS.

Currently, a novel coronavirus (2019-nCoV) causes an outbreak of viral pneumonia in Hubei province, China. In this paper, stochastic and deterministic models are proposed to investigate the transmission mechanism of 2019-nCoV from 15 January to 5 February 2020 in Hubei province. For the deterministic model, basic reproduction number R0 is defined and endemic equilibrium is given. Under R0>1, quasi-stationary distribution of the stochastic process is approximated by Gaussian diffusion. Residual, sensitivity, dynamical, and diffusion analyses of the models are conducted. Further, control variables are introduced to the deterministic model and optimal strategies are provided. Based on empirical results, we suggest that the first and most important thing is to control input, screening, treatment, and isolation.

BACKGROUND & AIMS: There is an urgent need for safe treatments for irritable bowel syndrome (IBS) that relieve treatment-refractory symptoms and their societal and economic burden. Cognitive behavior therapy (CBT) is an effective treatment that has not been broadly adopted into routine clinical practice. We performed a randomized controlled trial to assess clinical responses to home-based CBT compared with clinic-based CBT and patient education. METHODS: We performed a prospective study of 436 patients with IBS, based on Rome III criteria, at 2 tertiary centers from August 23, 2010 through October 21, 2016. Subjects (41.4±14.8 y old; 80% female) were randomly assigned groups that received: standard CBT (S-CBT, n=146, comprising 10 weekly, 60-min sessions that emphasized the provision of information about brain–gut interactions; self-monitoring of symptoms, their triggers, and consequences; muscle relaxation; worry control; flexible problem solving; and relapse prevention training), or 4 sessions of primarily home-based CBT requiring minimal therapist contact (MC-CBT, n=145), in which patients received home-study materials covering same procedures as S-CBT), or 4 sessions of IBS education (EDU, n=145) that provided support and information about IBS and the role of lifestyle factors such as stress, diet, exercise. The primary outcome was global improvement of IBS symptoms, based on the IBS-version of the Clinical Global Impressions-Improvement Scale. Ratings were performed by patients and board-certified gastroenterologists blinded to treatment allocation. Efficacy data were collected 2 weeks, 3 months, and 6 months after treatment completion. RESULTS: A higher proportion of patients receiving MC-CBT reported moderate to substantial improvement in gastrointestinal symptoms 2 weeks after treatment (61.0% based on ratings by patients and 55.7% based on ratings by gastroenterologists) than those receiving EDU (43.5% based on ratings patients and 40.4% based on ratings by gastroenterologists) (P

In ophthalmologic or otolaryngologic study, each subject may contribute paired organs measurements to the analysis. A number of statistical methods have been proposed on bilateral correlated data. In practice, it is important to detect confounding effect by treatment interaction, since ignoring confounding effect may lead to unreliable conclusion. Therefore, stratified data analysis can be considered to adjust the effect of confounder on statistical inference. In this article, we investigate and derive three test procedures for testing homogeneity of difference of two proportions for stratified correlated paired binary data in the basis of equal correlation model assumption. The performance of proposed test procedures is examined through Monte Carlo simulation. The simulation results show that the Score test is usually robust on type I error control with high power, and therefore is recommended among the three methods. One example from otolaryngologic study is given to illustrate the three test pr...

Correlated binary data arise in many ophthalmological and otolaryngological clinical trials. To test the homogeneity of prevalences among different groups is an important issue when conducting these trials. The equal correlation coefficients model proposed by Donner in 1989 is a popular model handling correlated binary data. The asymptotic chi-square test works well when the sample size is large. However, it would fail to maintain the type I error rate when the sample size is relatively small. In this paper, we propose several exact methods to deal with small sample scenarios. Their performances are compared with respect to type I error rate and power. The ‘M approach’ and the ‘E + M approach’ seem to outperform the others. A real work example is given to further explain how these approaches work. Finally, the computational efficiency of the exact methods is discussed as a pressing issue of future work.

Objective This study aimed to compare short-term respiratory outcomes of three steroids (dexamethasone, hydrocortisone, and methylprednisolone) to facilitate extubation by improving respiratory status in preterm infants.Study Design This is a retrospective, single-center, cohort study of 98 intubated preterm infants ≤346/7 weeks' gestation, admitted to a 64-bed, level III neonatal intensive care unit at the Women & Children's Hospital of Buffalo, Buffalo, NY, between 2006 and 2012, who received a short course of low-dose steroids for lung disease after first week of life.Results Study infants received dexamethasone (34%), hydrocortisone (44%), or methylprednisolone (22%) based on clinical team preference. By day 7 after initiation of steroids, extubation occurred in 59, 44, and 41%, respectively, in infants on dexamethasone, hydrocortisone, and methylprednisolone (p = 0.3). The mean respiratory severity score (RSS = fraction of inspired oxygen × mean airway pressure), a quantitative measure of respiratory status, decreased by 44% for all infants and by 59% in the dexamethasone group by day 7.Conclusion Steroids improved short-term respiratory outcomes in all infants (RSS and extubation); by day 7, dexamethasone treatment was associated with the greatest decrease in RSS. Additional prospective, randomized trials of short-course low-dose steroids are warranted to substantiate these findings to guide clinical decision making and in evaluating differential steroid effects on long-term neurodevelopmental outcomes.

In ophthalmological and otolaryngology studies, measurements obtained from both organs (e.g., eyes or ears) of an individual are often highly correlated. Ignoring the intraclass correlation between paired measurements may yield biased inferences. In this article, four different confidence interval (CI) construction methods (maximum likelihood estimates based Wald-type CI, profile likelihood CI, asymptotic score CI and an existing method adjusted for correlated bilateral data) are applied to this type of correlated bilateral data to construct CI for proportion ratio, taking the intraclass correlation into consideration. The coverage probabilities and widths of the resulting CIs are compared with each other in a Monte Carlo simulation study to evaluate their performances. A real dataset from an ophthalmologic study is used to illustrate our methodology.

BACKGROUND: There is a need for safe and effective IBS treatments that provide immediate and sustained improvement of IBS symptoms, particularly among more severe patients. The aim was to assess long-term clinical response of cognitive behavioral therapy (CBT) with reference to IBS education. METHODS: A total of 436 Rome III-diagnosed IBS patients (80% F, M age = 41 years) were randomized to: 4 session home-based CBT (minimal contact (MC-CBT)), 10 session clinic-based CBT (standard (S-CBT)), or 4 session IBS education (EDU). Follow-up occurred at 2 weeks and 3, 6, 9, and 12 months following treatment completion. Treatment response was based a priori on the Clinical Global Improvement Scale (global IBS symptom improvement) and IBS Symptom Severity Scale (IBS-SSS). RESULTS: Post-treatment CGI gains were generally maintained by MC-CBT patients at quarterly intervals through 12-month follow-up with negligible decay. For MC-CBT and S-CBT, 39 and 33% of respondents maintained treatment response at every follow-up assessment. The corresponding percent for EDU was 19%, which was significantly lower (p < 0.05) than for the CBT groups. On the IBS-SSS, therapeutic gains also showed a pattern of maintenance with trends towards increased efficacy over time in all conditions, with the mean unit reductions between baseline and follows-up being approximately −76 at immediate and approximately −94 at 12 months (−50 = clinically significant). CONCLUSIONS: For treatment-refractory IBS patients, home-and clinic-based CBT resulted in substantial and enduring relief of multiple IBS symptoms that generally extended to 12-month post treatment.

We consider four exact procedures to test the homogeneity of proportions for correlated multiple clustered data. Exact procedures are compared with the asymptotic approach based on the score statis...

This paper proposes asymptotic and exact methods for testing the equality of correlations for multiple bilateral data under Dallal’s model. Three asymptotic test statistics are derived for large samples. Since they are not applicable to small data, several conditional and unconditional exact methods are proposed based on these three statistics. Numerical studies are conducted to compare all these methods with regard to type I error rates (TIEs) and powers. The results show that the asymptotic score test is the most robust, and two exact tests have satisfactory TIEs and powers. Some real examples are provided to illustrate the effectiveness of these tests.

In stratified bilateral studies, responses from two paired body parts are correlated. Confidence intervals (CIs), which reveal various features of the data, should take the correlations into account. In this article, five CI methods (sample-size weighted naive Maximum likelihood estimation (MLE)-based Wald-type CI, complete MLE-based Wald-type CI, profile likelihood CI, MLE-based score CI and pooled MLE-based Wald-type CI) are derived for proportion ratios under the assumption of equal correlation coefficient within each stratum. Monte Carlo simulation shows that the complete MLE-based Wald-type CI approach generally produces the shortest mean interval width and satisfactory empirical coverage probability with close form solution; while the profile likelihood CI and the MLE-based score CI provide preferred ratio of non coverage probability and are more symmetric. Two real examples are used to demonstrate the performance of the proposed methods.

Bilateral correlated data are often encountered in medical researches such as ophthalmologic (or otolaryngologic) studies, in which each unit contributes information from paired organs to the data analysis, and the measurements from such paired organs are generally highly correlated. Various statistical methods have been developed to tackle intra-class correlation on bilateral correlated data analysis. In practice, it is very important to adjust the effect of confounder on statistical inferences, since either ignoring the intra-class correlation or confounding effect may lead to biased results. In this article, we propose three approaches for testing common risk difference for stratified bilateral correlated data under the assumption of equal correlation. Five confidence intervals of common difference of two proportions are derived. The performance of the proposed test methods and confidence interval estimations is evaluated by Monte Carlo simulations. The simulation results show that the score test statistic outperforms other statistics in the sense that the former has robust type [Formula: see text] error rates with high powers. The score confidence interval induced from the score test statistic performs satisfactorily in terms of coverage probabilities with reasonable interval widths. A real data set from an otolaryngologic study is used to illustrate the proposed methodologies.

Introduction Statins reduce cardiovascular disease risk and are generally well tolerated, yet up to 0.5% of statin-treated patients develop incapacitating muscle symptoms including rhabdomyolysis. Our objective was to identify clinical factors related to statin-associated muscle symptoms (SAMS). Methods Clinical and laboratory characteristics were evaluated in 748 statin-treated Caucasians (634 with SAMS and 114 statin-tolerant controls). Information was collected on statin type, concomitant drug therapies, muscle symptom history, comorbidities, and family history. Logistic regression was used to identify associations. Results Individuals with SAMS were 3.6 times (odds ratio [OR] 3.60, 95% confidence interval [CI] 2.08-6.22) more likely than statin-tolerant controls to have a family history of heart disease. Additional associations included obesity (OR 3.08, 95% CI 1.18, 8.05), hypertension (OR 2.24, 95% CI 1.33, 3.77), smoking (OR 2.08, 95% CI 1.16, 3.74), and statin type. Discussion Careful medical monitoring of statin-treated patients with the associated coexisting conditions may ultimately reduce muscle symptoms and lead to improved compliance. Muscle Nerve 59:537-537, 2019.

Homogeneity is a nonnegligible condition in the statistical analysis of the stratified bilateral data. The correlation between responses from two paired body parts should be taken into account to avoid biased or misleading results. In this article, we derive four test statistics (i.e., likelihood ratio statistic TL, Wald-type statistic TW, and score statistics TSCa and TSCb) for testing common ratios of two proportions across strata under the assumption of equal correlation coefficient within each stratum. Monte Carlo simulations show that the score test (TSCb) generally produces robust Type I error and satisfactory power. Two real examples are used to demonstrate the performance of the four proposed tests. Supplementary materials for this article are available online.

Summary Statin-induced myopathy (SIM) is the most common reason for discontinuation of statin therapy. A polymorphism affecting the gene encoding glycine amidinotransferase ( GATM rs9806699 G > A) was previously associated with reduced risk for SIM. Our objective was to replicate the GATM association in a large, multicenter SIM case-control study. Mild and severe SIM cases and age- and gender-matched controls were enrolled. Participants were genotyped, and associations were tested (n = 715) using chi-square and logistic regression with consideration for SIM severity and exclusion of subjects with potentially confounding comedications. The minor allele (A) frequencies of GATM rs9806699 in the controls (n = 106), mild SIM (n = 324), and severe SIM (n = 285) cases were 0.26, 0.28, and 0.29, respectively (p = 0.447). The unadjusted odds ratio for the A allele for any SIM (mild or severe) was 1.14 (0.82–1.61; p = 0.437), which remained nonsignificant in all models. Our results do not replicate the association between GATM rs9806699 and SIM.

Background: The oxygenation index (OI = mean airway pressure, MAP × FiO2 × 100 : PaO2) is used to assess the severity of hypoxic respiratory failure (HRF) and persistent pulmonary hypertension of the newborn (PPHN). An indwelling arterial line or arterial punctures are necessary to obtain PaO2 for the calculation of OI. Oxygenation can be continuously and noninvasively assessed using pulse oximetry. The use of the oxygen saturation index (OSI = MAP × FiO2 × 100 : SpO2) can be an alternate method of assessing the severity of HRF. Objective: To evaluate the correlation between OSI and OI in the following: (1) neonates with HRF and (2) a lamb model of meconium aspiration syndrome. Methods: Human neonates: a retrospective chart review of 74 ventilated late preterm/term neonates with indwelling arterial access and SpO2 values in the first 24 h of life was conducted. OSI and OI were calculated and correlated. Lamb model: arterial blood gases were drawn and preductal SpO2 was documented in 40 term newborn lambs with asphyxia and meconium aspiration. OI and OSI were calculated and correlated with pulmonary vascular resistance (PVR). Results: Mean values of OSI and OI showed a correlation coefficient of 0.952 in neonates (mean value of 308 observations in 74 neonates) and 0.948 in lambs (mean value of 743 observations in 40 lambs). In lambs, with increasing PVR, there was a decrease in OI and OSI. Conclusion: OSI correlates significantly with OI in infants with HRF. This noninvasive measure may be used to assess the severity of HRF and PPHN in neonates without arterial access.

BACKGROUND: The objective of this work was to describe the use of negative-pressure ventilation (NPV) in a heterogeneous critically ill, pediatric population. METHODS: A retrospective chart review was conducted of all patients admitted to a pediatric ICU with acute respiratory failure supported with NPV from January 1, 2012 to May 15, 2015. RESULTS: Two hundred thirty-three subjects at a median age of 15.5 months were supported with NPV for various etiologies, most commonly bronchiolitis (70%). Median (interquartile range) duration of support was 18.7 (8.7–34.3) h. The majority were NPV responders (70%), defined as not needing escalation to any form of positive-pressure ventilation. In non-responders, escalation occurred at a median (interquartile range) of 6.9 (3.3–16.6) h. More NPV non-responders had upper-airway obstruction (P = .02), and fewer had bronchiolitis (P = .008) compared with responders. A bedside scoring system developed on these data was 98% specific in predicting NPV failure by 4 h after NPV start (area under the curve 0.759, 95% CI 0.675–0.843, P CONCLUSIONS: NPV is a noninvasive respiratory support for pediatric acute respiratory failure from all causes with few complications and a 70% response rate. Children receiving NPV often required intravenous sedation for comfort, and one third received delayed enteral nutrition. Those who required escalation from NPV worsened within 6 h; this may be predictable with a bedside scoring system.

Because irritable bowel syndrome (IBS) is a functional medical condition for which there is no curative therapy, treatment goals emphasize relieving gastrointestinal (GI) symptoms and optimizing the quality of life (QOL). This study sought to characterize the magnitude of the associations between QOL impairment, fear of IBS symptoms, and confounding variables.Subjects included 234 Rome III-diagnosed IBS patients (mean age, 41 years, 79%, female) without comorbid organic GI disease who were referred to two specialty care clinics of an National Institutes of Health trial for IBS. Subjects completed a testing battery that included the IBS-specific QOL (IBS-QOL), SF-12 (generic QOL), the UCLA GI Symptom Severity Scale, the Visceral Sensitivity Index, Trait Anxiety Inventory, and Brief Symptom Inventory.Multiple linear regression was used to develop a model for predicting QOL. Data supported an overall model that included sociodemographic, clinical (e.g., current severity of GI symptoms), and psychosocial (e.g., fear of GI symptoms, distress, neuroticism) variables, accounting for 48.7% of the variance in IBS-QOL (F=15.1, P0.01). GI symptom fear was the most robust predictor of IBS-QOL (β=-0.45 P0.01), accounting for 14.4% of the total variance.Patients' fear that GI symptoms have aversive consequences, is a predictor of QOL impairment that cannot be fully explained by the severity of their GI symptoms, overall emotional well-being, neurotic personality style, or other clinical features of IBS. An understanding of the unique impact that GI symptom fears have on QOL can inform treatment planning and help gastroenterologists to better manage more severe IBS patients seen in tertiary care clinics.

For binary clustered data with cluster size of two, which often arises from otolaryngologic and ophthalmologic studies, the correlation between the outcomes is usually unknown. For this reason, an asymptotic approach based on normal approximation has been often used for comparing proportions between groups. This approach performs poorly with unacceptable Type I error control in small sample settings. Storer and Kim proposed an approximate unconditional method to control the Type I error associated with the asymptotic approach. However, both the asymptotic approach and the approximate unconditional approach do not guarantee the test size. Exact tests may be considered as alternatives to control the Type I error. Tang et al. studied the unconditional approach based on maximization for this type of data. It was shown to be overly conservative in most cases. We present two exact approaches to reduce the conservativeness of the exact test based on maximization: one is a conditional approach and the other is an...

BACKGROUND & AIMS: Among patients with irritable bowel syndrome (IBS), it would be helpful to identify those most likely to respond to specific treatments, yet few factors have been identified that reliably predict positive outcome. We sought to identify pretreatment baseline characteristics that associate with symptom improvement in patients who received empirically validated regimens of cognitive behavior therapy (CBT) or IBS education. METHODS: We analyzed data from the IBS Outcome Study, in which 436 patients with IBS (average age, 41 years; 80% female) were randomly assigned to groups that received to 4 or 10 weeks of cognitive behavior therapy or education. Baseline data were collected from all participants on sociodemographic and clinical features and comorbidities. Interaction analyses used a modified linear probability model with Huber-White robust estimators to identify baseline factors that moderated as a function of treatment condition symptom improvement based on the IBS-version of the Clinical Global Impressions-Improvement Scale. RESULTS: Whether the primary outcome of IBS symptom improvement was rated by patients or physician assessors blind to treatment 2 weeks after it ended, higher percentages of patients had symptom improvement after CBT compared with EDU among those with low levels of trait anxiety (71.3% vs 34.9%; P

Background & Aims Irritable bowel syndrome (IBS) has significant mental and physical comorbidities. However, little is known about the day-to-day burden these comorbidities place on quality of life (QOL), physical and mental function, distress, and symptoms of patients. Methods We collected cross-sectional data from 175 patients with IBS, which was diagnosed on the basis of Rome III criteria (median age, 41 years; 78% women), who were referred to 2 specialty care clinics. Patients completed psychiatric interviews, a physical comorbidity checklist, the IBS Symptom Severity Scale, the IBS-QOL instrument, the Brief Symptom Inventory, the abdominal pain intensity scale, and the Short Form-12 Health Survey. Results Patients with IBS reported an average of 5 comorbidities (1 mental, 4 physical). Subjects with more comorbidities reported worse QOL after adjusting for confounding variables. Multiple linear regression analyses indicated that comorbidity type was more consistently and strongly associated with illness burden indicators than disease counts. Of 10,296 possible physical-mental comorbidity pairs, 6 of the 10 most frequent dyads involved specific conditions (generalized anxiety, depression, back pain, agoraphobia, tension headache, and insomnia). These combinations were consistently associated with greater illness and symptom burdens (QOL, mental and physical function, distress, more severe symptoms of IBS, and pain). Conclusions Comorbidities are common among patients with IBS. They are associated with distress and reduced QOL. Specific comorbidities are associated with more severe symptoms of IBS.

Irritable bowel syndrome is a common, oftentimes disabling, gastrointestinal disorder whose full range of symptoms has no satisfactory medical or dietary treatment. One of the few empirically validated treatments includes a specific psychological therapy called cognitive behavior therapy which, if available, is typically administered over several months by trained practitioners in tertiary care settings. There is an urgent need to develop more efficient versions of CBT that require minimal professional assistance but retain the efficacy profile of clinic based CBT. The Irritable Bowel Syndrome Outcome Study (IBSOS) is a multicenter, placebo-controlled randomized trial to evaluate whether a self-administered version of CBT is, at least as efficacious as standard CBT and more efficacious than an attention control in reducing core GI symptoms of IBS and its burden (e.g. distress, quality of life impairment, etc.) in moderately to severely affected IBS patients. Additional goals are to assess, at quarterly intervals, the durability of treatment response over a 12 month period; to identify clinically useful patient characteristics associated with outcome as a way of gaining an understanding of subgroups of participants for whom CBT is most beneficial; to identify theory-based change mechanisms (active ingredients) that explain how and why CBT works; and evaluate the economic costs and benefits of CBT. Between August 2010 when IBSOS began recruiting subjects and February 2012, the IBSOS randomized 171 of 480 patients. Findings have the potential to improve the health of IBS patients, reduce its social and economic costs, conserve scarce health care resources, and inform evidence-based practice guidelines.

The effect of the cystic fibrosis transmembrane conductance regulator protein (CFTR) defect in pancreatic insufficient (PI) patients with cystic fibrosis (CF) on the gastrointestinal pH profile is poorly defined. Adequate and efficient neutralization of the gastric acidity in the duodenum is important for nutrient absorption and timely release of pancreatic enzyme replacement therapy (PERT). We utilized a wireless motility capsule (WMC) to study intestinal pH profile and gastrointestinal transit profile in CF subjects. WMC studies were done on ten adult CF patients with PI while off acid suppression medication and ten age, gender and BMI matched healthy controls. Mean pH over 1 min increments and area under the pH curve over 5 min increments was calculated for the first hour post gastric emptying. Paired t-test was used to compare means of the pH recordings, transit profiles and analysis of time interval required to reach and maintain pH >5.5 and 6.0. A statistically significant difference was observed between mean pH values during the first 23 min of small bowel transit (p

A major limiting factor in much of the epidemiological and environmental researches is the cost of measuring the biomarkers or analytes of interest. Often, the number of specimens available for analysis is greater than the number of assays that is budgeted for. These assays are then performed on a random sample of specimens. Regression calibration is then utilized to infer biomarker levels of expensive assays from other correlated biomarkers that are relatively inexpensive to obtain and analyze. In other contexts, use of pooled specimens has been shown to increase efficiency in estimation. In this article, we examine two types of pooling in lieu of a random sample. The first is random (or traditional) pooling, and we characterize the second as “optimal” pooling. The second, which we propose for regression analysis, is pooling based on specimens ranked on the less expensive biomarker. The more expensive assay is then performed on the pool of relatively similar measurements. The optimal nature of this techn...

Introduction: Of the nearly 38 million people in the USA who receive statin therapy, 0.1-0.5% experience severe or life-threatening myopathic side effects. Methods: We performed a genome-wide association study (GWAS) in a group of patients with severe statin myopathy versus a statin-tolerant group to identify genetic susceptibility loci. Results: Replication studies in independent groups of severe statin myopathy (n = 190) and statin-tolerant controls (n = 130) resulted in the identification of three single-nucleotide polymorphisms (SNPs), rs9342288, rs1337512, and rs3857532, in the eyes shut homolog (EYS) on chromosome 6 suggestive of an association with risk for severe statin myopathy (P = 0.0003–0.0008). Analysis of EYS cDNA demonstrated that EYS gene products are complex and expressed with relative abundance in the spinal cord as well as in the retina. Conclusion: Structural similarities of these EYS gene products to members of the Notch signaling pathway and to agrin suggest a possible functional role in the maintenance and regeneration of the structural integrity of skeletal muscle. Muscle Nerve, 2011

Aerosolized prostacyclin (PGI2) produces selective pulmonary vasodilation in patients with pulmonary hypertension (PH). The response to PGI2may be increased by phosphodiesterase type 3 inhibitors such as milrinone. We studied the dose response effects of aerosolized PGI2and aerosolized milrinone both alone and in combination on pulmonary and systemic hemodynamics in newborn lambs with Nω-nitro-l-arginine methyl ester (l-NAME)-induced PH. We hypothesized that coaerosolization of PGI2with milrinone would additively decrease pulmonary vascular resistance (PVR), prolong the duration of action of PGI2, and selectively dilate the pulmonary vasculature. Near-term lambs were delivered by C-section and instrumented and PH was induced by l-NAME (bolus 25 mg/kg; infusion 10 mg·kg−1·h−1) and indomethacin. In the first set of experiments, PGI2was aerosolized at random doses of 2, 20, 100, 200, 500, and 1,000 ng·kg−1·min−1followed by milrinone at doses of 0.1, 1, and 10 μg·kg−1·min−1over 10 min. In the second set of experiments, milrinone at 1 μg·kg−1·min−1was aerosolized in combination with PGI2at doses of 20, 100, and 200 ng·kg−1·min−1over 10 min. Pulmonary arterial pressures (PAP) and PVR decreased significantly with increasing doses of aerosolized PGI2and milrinone. The combination of PGI2and milrinone significantly reduced PAP and PVR more than either of the drugs aerosolized alone. Addition of milrinone significantly increased the duration of action of PGI2. When aerosolized independently, PGI2and milrinone selectively dilated the pulmonary vasculature but the combination did not. Milrinone enhances the vasodilatory effects of PGI2on the pulmonary vasculature but caution must be exercised regarding systemic hypotension.

It has been recognized that genetic mutations in specific nucleotides may give rise to cancer via the alteration of signaling pathways. Thus, the detection of those cancer-causing mutations has received considerable interest in cancer genetic research. Here, we propose a statistical model for characterizing genes that lead to cancer through point mutations using genome-wide single nucleotide polymorphism (SNP) data. The basic idea of the model is that mutated genes may be in high association with their nearby SNPs because of evolutionary forces. By genotyping SNPs in both normal and cancer cells, we formulate a polynomial likelihood to estimate the population genetic parameters related to cancer, such as allele frequencies of cancer-causing alleles, mutation rates of alleles derived from maternal or paternal parents, and zygotic linkage disequilibria between different loci after the mutation occurs. We implement the EM algorithm to estimate some of these parameters because of the missing information in the likelihood construction. The model allows the elegant tests of the significant associations between mutated cancer genes and genome-wide SNPs, thus providing a way for predicting the occurrence and formation of cancer with genetic information. The model, validated through computer simulation, may help cancer geneticists design efficient experiments and formulate hypotheses for cancer gene identification.