Interval estimation of relative risks for combined unilateral and bilateral correlated data.

Measurements are generally collected as unilateral or bilateral data in clinical trials, epidemiology, or observational studies. For example, in ophthalmology studies, the primary outcome is often obtained from one eye or both eyes of an individual. In medical studies, the relative risk is usually the parameter of interest and is commonly used. In this article, we develop three confidence intervals for the relative risk for combined unilateral and bilateral correlated data under the equal dependence assumption. The proposed confidence intervals are based on maximum likelihood estimates of parameters derived using the Fisher scoring method. Simulation studies are conducted to evaluate the performance of proposed confidence intervals with respect to the empirical coverage probability, the mean interval width, and the ratio of mesial non-coverage probability to the distal non-coverage probability. We also compare the proposed methods with the confidence interval based on the method of variance estimates recovery and the confidence interval obtained from the modified Poisson regression model with correlated binary data. We recommend the score confidence interval for general applications because it best controls converge probabilities at the 95% level with reasonable mean interval width. We illustrate the methods with a real-world example.

Fixed dose ketamine for prehospital management of hyperactive delirium with severe agitation.

INTRODUCTION: Patients exhibiting signs of hyperactive delirium with severe agitation (HDSA) may require sedating medications for stabilization and safe transport to the hospital. Determining the patient's weight and calculating the correct weight-based dose may be challenging in an emergency. A fixed dose ketamine protocol is an alternative to the traditional weight-based administration, which may also reduce dosing errors. The objective of this study was to evaluate the frequency and characteristics of adverse events following pre-hospital ketamine administration for HDSA. METHODS: Emergency Medical Services (EMS) records from four agencies were searched for prehospital ketamine administration. Cases were included if a 250 mg dose of ketamine was administered on standing order to an adult patient for clinical signs consistent with HDSA. Protocols allowed for a second 250 mg dose of ketamine if the first dose was not effective. Both the 250 mg initial dose and the total prehospital dose were analyzed for weight based dosing and adverse events. RESULTS: Review of 132 cases revealed 60 cases that met inclusion criteria. Patients' median weight was 80 kg (range: 50-176 kg). No patients were intubated by EMS, one only requiring suction, three required respiratory support via bag valve mask (BVM). Six (10%) patients were intubated in the emergency department (ED) including the three (5%) supported by EMS via BVM, three (5%) others who were sedated further in the ED prior to requiring intubation. All six patients who were intubated were discharged from the hospital with a Cerebral Performance Category (CPC) 1 score. The weight-based dosing equivalent for the 250 mg initial dose (OR: 2.62, CI: 0.67-10.22) and the total prehospital dose, inclusive of the 12 patients that were administered a second dose, (OR: 0.74, CI: 0.27, 2.03), were not associated with the need for intubation. CONCLUSION: The 250 mg fixed dose of ketamine was not >5 mg/kg weight-based dose equivalent for all patients in this study. Although a second 250 mg dose of ketamine was permitted under standing orders, only 12 (20%) of the patients were administered a second dose, none experienced an adverse event. This indicates that the 250 mg initial dose was effective for 80% of the patients. Four patients with prehospital adverse events likely related to the administration of ketamine were found. One required suction, three (5%) requiring BVM respiratory support by EMS were subsequently intubated upon arrival in the ED. All 60 patients were discharged from the hospital alive. Further research is needed to determine an optimal single administration dose for ketamine in patients exhibiting signs of HDSA, if employing a standardized fixed dose medication protocol streamlines administration, and if the fixed dose medication reduces the occurrence of dosage errors.

Testing the homogeneity of proportions for combined unilateral and bilateral data.

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.

Fast QLB algorithm and hypothesis tests in logistic model for ophthalmologic bilateral correlated data.

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.

Improvement in Gastrointestinal Symptoms After Cognitive Behavior Therapy for Refractory Irritable Bowel Syndrome.

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 years old; 80% women) were randomly assigned to groups that received the following: standard-CBT (S-CBT, n = 146, comprising 10 weekly, 60-minute 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 the 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, and 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 < .05). Gastrointestinal symptom improvement, rated by gastroenterologists, 6 months after the end of treatment also differed significantly between the MC-CBT (58.4%) and EDU groups (44.8%) (P = .05). Formal equivalence testing applied across multiple contrasts indicated that MC-CBT is at least as effective as S-CBT in improving IBS symptoms. Patients tended to be more satisfied with CBT vs EDU (P < .05) based on immediate posttreatment responses to the Client Satisfaction Questionnaire. Symptom improvement was not significantly related to concomitant use of medications. CONCLUSIONS: In a randomized controlled trial, we found that a primarily home-based version of CBT produced significant and sustained gastrointestinal symptom improvement for patients with IBS compared with education. Clinicaltrials.gov no.: NCT00738920.

Durability and Decay of Treatment Benefit of Cognitive Behavioral Therapy for Irritable Bowel Syndrome: 12-Month Follow-Up.

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.

Confidence intervals for proportion ratios of stratified correlated bilateral data.

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 naïve 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.

Asymptotic confidence interval construction for proportion ratio based on correlated paired data.

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.

Testing equality of proportions for correlated binary data in ophthalmologic studies.

In ophthalmologic studies, bilateral correlated data often arise when information involving paired organs (e.g., eyes) are measured from each subject. Adjusted chi-square approach for testing the equality of proportions has been proposed in the literature. In this article, we investigate and derive three alter- native testing procedures for the problem. Our simulation results show the score testing procedure usually produces satisfactory type I error control with higher power, and therefore is recommended. Examples from ophthalmologic studies are used to illustrate our proposed methods.

Fear of GI symptoms has an important impact on quality of life in patients with moderate-to-severe IBS.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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, P <0.01). GI symptom fear was the most robust predictor of IBS-QOL (ß=-0.45 P <0.01), accounting for 14.4% of the total variance. CONCLUSIONS: 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.

Type, rather than number, of mental and physical comorbidities increases the severity of symptoms in patients with irritable bowel syndrome.

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.

Homogeneity test of relative risk ratios for stratified bilateral data under different algorithms.

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. T L , T S C and T W ) 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, T S C is recommended according to its robust TIEs and satisfactory power.

National Variation in EMS Response and Antiepileptic Medication Administration for Children with Seizures in the Prehospital Setting.

BACKGROUND AND OBJECTIVES: Prehospital Advanced Life Support (ALS) is important to improve patient outcomes in children with seizures, yet data is limited regarding national prehospital variation in ALS response for these children. We aimed to determine the variation in ALS response and prehospital administration of antiepileptic medication for children with seizures across the United States. METHODS: We analyzed children <19 years with 9-1-1 dispatch codes for seizure in the 2019 National Emergency Medical Services Information System dataset. We defined ALS response as ALS-paramedic, ALS-Advanced Emergency Medical Technician, or ALS-intermediate responses. We conducted regression analyses to identify associations between ALS response (primary outcome), antiepileptic administration (secondary outcome) and age, gender, location, and US census regions. RESULTS: Of 147,821 pediatric calls for seizures, 88% received ALS responses. Receipt of ALS response was associated with urbanicity, with wilderness (adjusted odds ratio [aOR] 0.44, 0.39-0.49) and rural (aOR 0.80, 0.75-0.84) locations less likely to have ALS responses than urban areas. Of 129,733 emergency medical service (EMS) activations with an ALS responder's impression of seizure, antiepileptic medications were administered in 9%. Medication administration was independently associated with age (aOR 1.008, 95% confidence interval [CI] 1.005-1.010) and gender (aOR 1.22, 95% CI 1.18-1.27), with females receiving medications more than males. Of the 11,698 children who received antiepileptic medications, midazolam was the most commonly used (83%). CONCLUSION: The majority of children in the US receive ALS responses for seizures. Although medications are infrequently administered, the majority who received medications had midazolam given, which is the current standard of care. Further research should determine the proportion of children who are continuing to seize upon EMS arrival and would most benefit from immediate treatment.

Simultaneous confidence interval construction for many-to-one comparisons of proportion differences based on correlated paired data.

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.

Fluctuation analysis CalculatOR: a web tool for the determination of mutation rate using Luria-Delbruck fluctuation analysis.

SUMMARY: The program Fluctuation AnaLysis CalculatOR (FALCOR) is a web tool designed for use with Luria-Delbrück fluctuation analysis to calculate the frequency and rate from various mutation assays in bacteria and yeast. Three calculation methods are available through this program: (i) Ma-Sandri-Sarkar Maximum Likelihood Estimator (MSS-MLE) method, (ii) Lea-Coulson method of the median (LC) and (iii) frequency. AVAILABILITY: The FALCOR rate calculator is currently accessible at http://www.mitochondria.org/protocols/FALCOR.html. This program is written as a Java Applet, requiring a web browser enabled with Sun MicroSystems' Java Virtual Machine.

Interval estimation of proportion ratios for stratified bilateral correlated binary data.

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.

A statistical model for testing the pleiotropic control of phenotypic plasticity for a count trait.

The differences of a phenotypic trait produced by a genotype in response to changes in the environment are referred to as phenotypic plasticity. Despite its importance in the maintenance of genetic diversity via genotype-by-environment interactions, little is known about the detailed genetic architecture of this phenomenon, thus limiting our ability to predict the pattern and process of microevolutionary responses to changing environments. In this article, we develop a statistical model for mapping quantitative trait loci (QTL) that control the phenotypic plasticity of a complex trait through differentiated expressions of pleiotropic QTL in different environments. In particular, our model focuses on count traits that represent an important aspect of biological systems, controlled by a network of multiple genes and environmental factors. The model was derived within a multivariate mixture model framework in which QTL genotype-specific mixture components are modeled by a multivariate Poisson distribution for a count trait expressed in multiple clonal replicates. A two-stage hierarchic EM algorithm is implemented to obtain the maximum-likelihood estimates of the Poisson parameters that specify environment-specific genetic effects of a QTL and residual errors. By approximating the number of sylleptic branches on the main stems of poplar hybrids by a Poisson distribution, the new model was applied to map QTL that contribute to the phenotypic plasticity of a count trait. The statistical behavior of the model and its utilization were investigated through simulation studies that mimic the poplar example used. This model will provide insights into how genomes and environments interact to determine the phenotypes of complex count traits.

Oxygen concentration and pulmonary hemodynamics in newborn lambs with pulmonary hypertension.

The effect of oxygen concentration on lowering pulmonary vascular resistance (PVR) during resuscitation in a model of persistent pulmonary hypertension of the newborn (PPHN) is not known. PPHN was induced in fetal lambs by ductal ligation 9 d before delivery. After delivery by cesarean section, resuscitation of PPHN lambs with 21%, 50%, or 100% O2 (n = 6 each) for 30 min produced similar decreases in PVR. Lambs were then ventilated with 50% O2 for 60 min and exposed to inhaled nitric oxide (iNO, 20 ppm). Initial resuscitation with 100% O2 significantly impaired the subsequent response to iNO compared with 21% O2 (42 +/- 9% vs 22 +/- 4% decrease from baseline PVR). Finally, each lamb was randomly and sequentially ventilated with 10%, 21%, 50%, or 100% O2. PVR decreased with increased concentrations of inhaled O2 up to 50%, there being no additional decrease in PVR with 100% O2. When PVR was correlated with Pao2, the maximal change in PVR was achieved at Pao2 values <60 mm Hg. We conclude that resuscitation with 100% O2 does not enhance pulmonary vasodilation compared with 21% and 50% O2, but impairs the subsequent response to iNO in PPHN lambs. Hypoxia increases PVR but hyperoxia does not confer significant additional pulmonary vasodilation in lambs with PPHN.

Common risk difference test and interval estimation of risk difference for stratified bilateral correlated data.

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 I 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.

Modeling the Genetic Control of HIV-1 Dynamics After Highly Active Antiretroviral Therapy.

The progression of HIV disease has been markedly slowed by the use of highly active antiretroviral therapy (HAART). However, substantial genetic variation was observed to occur among different people in the decay rate of viral loads caused by HAART. The characterization of specific genes involved in HIV dynamics is central to design personalized drugs for the prevention of this disease, but usually cannot be addressed by experimental methods alone rather than require the help of mathematical and statistical methods. A novel statistical model has been recently developed to detect genetic variants that are responsible for the shape of HAART-induced viral decay curves. This model was employed to an HIV/AIDS trial, which led to the identification of a major genetic determinant that triggers an effect on HIV dynamics. This detected major genetic determinant also affects several clinically important parameters, such as half-lives of infected cells and HIV eradication times.