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Concept: Interval estimation


Background Apixaban, an oral factor Xa inhibitor administered in fixed doses, may simplify the treatment of venous thromboembolism. Methods In this randomized, double-blind study, we compared apixaban (at a dose of 10 mg twice daily for 7 days, followed by 5 mg twice daily for 6 months) with conventional therapy (subcutaneous enoxaparin, followed by warfarin) in 5395 patients with acute venous thromboembolism. The primary efficacy outcome was recurrent symptomatic venous thromboembolism or death related to venous thromboembolism. The principal safety outcomes were major bleeding alone and major bleeding plus clinically relevant nonmajor bleeding. Results The primary efficacy outcome occurred in 59 of 2609 patients (2.3%) in the apixaban group, as compared with 71 of 2635 (2.7%) in the conventional-therapy group (relative risk, 0.84; 95% confidence interval [CI], 0.60 to 1.18; difference in risk [apixaban minus conventional therapy], -0.4 percentage points; 95% CI, -1.3 to 0.4). Apixaban was noninferior to conventional therapy (P<0.001) for predefined upper limits of the 95% confidence intervals for both relative risk (<1.80) and difference in risk (<3.5 percentage points). Major bleeding occurred in 0.6% of patients who received apixaban and in 1.8% of those who received conventional therapy (relative risk, 0.31; 95% CI, 0.17 to 0.55; P<0.001 for superiority). The composite outcome of major bleeding and clinically relevant nonmajor bleeding occurred in 4.3% of the patients in the apixaban group, as compared with 9.7% of those in the conventional-therapy group (relative risk, 0.44; 95% CI, 0.36 to 0.55; P<0.001). Rates of other adverse events were similar in the two groups. Conclusions A fixed-dose regimen of apixaban alone was noninferior to conventional therapy for the treatment of acute venous thromboembolism and was associated with significantly less bleeding (Funded by Pfizer and Bristol-Myers Squibb; number, NCT00643201 ).

Concepts: Normal distribution, Interval estimation, Confidence interval, Bristol-Myers Squibb


Study design:Cross-sectional validation study.Objectives:To develop and validate a self-report version of the Spinal Cord Independence Measure (SCIM III).Setting:Two SCI rehabilitation facilities in Switzerland.Methods:SCIM III comprises 19 questions on daily tasks with a total score between 0 and 100 and subscales for ‘self-care’, ‘respiration & sphincter management’ and ‘mobility’. A self-report version (SCIM-SR) was developed by expert discussions and pretests in individuals with spinal cord injury (SCI) using a German translation. A convenience sample of 99 inpatients with SCI was recruited. SCIM-SR data were analyzed together with SCIM III data obtained from attending health professionals.Results:High correlations between SCIM III and SCIM-SR were observed. Pearson’s r for the total score was 0.87 (95% confidence interval (CI) 0.82-0.91), for the subscales self-care 0.87 (0.81-0.91); respiration & sphincter management 0.81 (0.73-0.87); and mobility 0.87 (0.82-0.91). Intraclass correlations were: total score 0.90 (95% CI 0.85-0.93); self-care 0.86 (0.79-0.90); respiration & sphincter management 0.80 (0.71-0.86); and mobility 0.83 (0.76-0.89). Bland-Altman plots showed that patients rated their functioning higher than professionals, in particular for mobility. The mean difference between SCIM-SR and SCIM III for the total score was 5.14 (point estimate 95% CI 2.95-7.34), self-care 0.89 (0.19-1.59), respiration & sphincter management 1.05 (0.18-2.28 ) and mobility 3.49 (2.44-4.54). Particularly patients readmitted because of pressure sores rated their independence higher than attending professionals.Conclusion:Our results support the criterion validity of SCIM-SR. The self-report version may facilitate long-term evaluations of independence in persons with SCI in their home situation.

Concepts: Spinal cord injury, The Criterion, Validation, Pearson product-moment correlation coefficient, Statistical inference, Statistics, Interval estimation, Criterion validity


AIM: Botulinum toxin A (BoNT-A) combined with occupational therapy is effective in improving upper limb outcomes in children with unilateral cerebral palsy (CP). It is now essential to identify the most effective therapies following BoNT-A. Given the added burden for children and families, the aim of this study was to explore whether modified constraint-induced movement therapy (mCIMT) leads to sufficiently superior gains compared with bimanual occupational therapy (BOT) in young children with unilateral CP following BoNT-A injections. METHOD: In this randomized, controlled, evaluator-blinded trial, 34 children (20 males, 14 females; mean age 3y, SD 1y 4mo, range 18mo-6y) with unilateral CP were randomized using concealed allocation to one of two 8-week interventions. The experimental group (n=17) received BoNT-A and mCIMT. The comparison group (n=17) received BoNT-A and BOT. Participants were recruited from a physical rehabilitation clinic and randomized between August 2003 and May 2009. Primary outcome was measured using the Assisting Hand Assessment at 3 months. Secondary outcomes were measured at 3 months and 6 months using the Quality of Upper Extremity Skills Test, the Pediatric Evaluation of Disability Inventory, Canadian Occupational Performance Measure, and the Goal Attainment Scale. RESULTS: There were no clinically important differences between groups at baseline. Immediately following intervention, there was no evidence of a superior effect for BoNT-A + mCIMT as determined by the Assisting Hand Assessment (estimated mean difference [EMD] 0.81, upper 95% confidence limit 3.6; p=0.32) or secondary outcomes. However, both groups showed improvement over time (BoNT-A + mCIMT: EMD 2.7, 95% confidence interval [CI] 0.7-5.2; BONT-A + BOT: EMD 4.7, 95% CI 2.1-8.6). Follow-up at 6 months also demonstrated no superior effect for BoNT-A + mCIMT. INTERPRETATION: Following upper limb injection of BoNT-A, there was no evidence that mCIMT, despite the significantly increased intensity of the home programme, produced a superior effect across a range of outcomes compared with a structured programme of BOT in young children with unilateral CP.

Concepts: Interval estimation, Measurement, Cerebral palsy, Confidence interval, Statistics, Limb, Canadian model of occupational performance, Upper limb


Background Early-phase and preclinical studies suggest that moxifloxacin-containing regimens could allow for effective 4-month treatment of uncomplicated, smear-positive pulmonary tuberculosis. Methods We conducted a randomized, double-blind, placebo-controlled, phase 3 trial to test the noninferiority of two moxifloxacin-containing regimens as compared with a control regimen. One group of patients received isoniazid, rifampin, pyrazinamide, and ethambutol for 8 weeks, followed by 18 weeks of isoniazid and rifampin (control group). In the second group, we replaced ethambutol with moxifloxacin for 17 weeks, followed by 9 weeks of placebo (isoniazid group), and in the third group, we replaced isoniazid with moxifloxacin for 17 weeks, followed by 9 weeks of placebo (ethambutol group). The primary end point was treatment failure or relapse within 18 months after randomization. Results Of the 1931 patients who underwent randomization, in the per-protocol analysis, a favorable outcome was reported in fewer patients in the isoniazid group (85%) and the ethambutol group (80%) than in the control group (92%), for a difference favoring the control group of 6.1 percentage points (97.5% confidence interval [CI], 1.7 to 10.5) versus the isoniazid group and 11.4 percentage points (97.5% CI, 6.7 to 16.1) versus the ethambutol group. Results were consistent in the modified intention-to-treat analysis and all sensitivity analyses. The hazard ratios for the time to culture negativity in both solid and liquid mediums for the isoniazid and ethambutol groups, as compared with the control group, ranged from 1.17 to 1.25, indicating a shorter duration, with the lower bounds of the 95% confidence intervals exceeding 1.00 in all cases. There was no significant difference in the incidence of grade 3 or 4 adverse events, with events reported in 127 patients (19%) in the isoniazid group, 111 (17%) in the ethambutol group, and 123 (19%) in the control group. Conclusions The two moxifloxacin-containing regimens produced a more rapid initial decline in bacterial load, as compared with the control group. However, noninferiority for these regimens was not shown, which indicates that shortening treatment to 4 months was not effective in this setting. (Funded by the Global Alliance for TB Drug Development and others; REMoxTB number, NCT00864383 .).

Concepts: AIDS, Normal distribution, Interval estimation, Confidence interval, Tuberculosis treatment, Clinical trial, Rifampicin, Tuberculosis


Interval estimates - estimates of parameters that include an allowance for sampling uncertainty - have long been touted as a key component of statistical analyses. There are several kinds of interval estimates, but the most popular are confidence intervals (CIs): intervals that contain the true parameter value in some known proportion of repeated samples, on average. The width of confidence intervals is thought to index the precision of an estimate; CIs are thought to be a guide to which parameter values are plausible or reasonable; and the confidence coefficient of the interval (e.g., 95 %) is thought to index the plausibility that the true parameter is included in the interval. We show in a number of examples that CIs do not necessarily have any of these properties, and can lead to unjustified or arbitrary inferences. For this reason, we caution against relying upon confidence interval theory to justify interval estimates, and suggest that other theories of interval estimation should be used instead.

Concepts: Interval finite element, Credible interval, Sample size, Confidence interval, Estimator, Interval estimation, Statistical inference, Statistics


Renal-cell carcinoma (RCC) affects over 330,000 new patients every year, of whom 1/3 present with metastatic RCC (mRCC) at diagnosis. Most mRCC patients treated with a first-line agent relapse within 1 year and need second-line therapy. The present study aims to compare overall survival (OS) between nivolumab and cabozantinib from two recent pivotal studies comparing, respectively, each one of the two emerging treatments against everolimus in patients who relapse following first-line treatment. Comparison is traditionally carried out using the Bucher method, which assumes proportional hazard. Since OS curves intersected in one of the pivotal studies, models not assuming proportional hazards were also considered to refine the comparison. Four Bayesian parametric survival network meta-analysis models were implemented on overall survival (OS) data digitized from the Kaplan-Meier curves reported in the studies. Three models allowing hazard ratios (HR) to vary over time were assessed against a fixed-HR model. The Bucher method favored cabozantinib, with a fixed HR for OS vs. nivolumab of 1.09 (95% confidence interval: [0.77, 1.54]). However, all models with time-varying HR showed better fits than the fixed-HR model. The log-logistic model fitted the data best, exhibiting a HR for OS initially favoring cabozantinib, the trend inverting to favor nivolumab after month 5 (95% credible interval <1 from 10 months). The initial probability of cabozantinib conferring superior OS was 54%, falling to 41.5% by month 24. Numerical differences in study-adjusted OS estimates between the two treatments remained small. This study evidences that HR for OS of nivolumab vs. cabozantinib varies over time, favoring cabozantinib in the first months of treatment but nivolumab afterwards, a possible indication that patients with poor prognosis benefit more from cabozantinib in terms of survival, nivolumab benefiting patients with better prognosis. More evidence, including real-world observational data, is needed to compare effectiveness between cabozantinib and nivolumab.

Concepts: Interval estimation, Statistical inference, Lung cancer, Confidence interval, Comparisons, Comparison, Credible interval, Renal cell carcinoma


Background Tuberculosis regimens that are shorter and simpler than the current 6-month daily regimen are needed. Methods We randomly assigned patients with newly diagnosed, smear-positive, drug-sensitive tuberculosis to one of three regimens: a control regimen that included 2 months of ethambutol, isoniazid, rifampicin, and pyrazinamide administered daily followed by 4 months of daily isoniazid and rifampicin; a 4-month regimen in which the isoniazid in the control regimen was replaced by moxifloxacin administered daily for 2 months followed by moxifloxacin and 900 mg of rifapentine administered twice weekly for 2 months; or a 6-month regimen in which isoniazid was replaced by daily moxifloxacin for 2 months followed by one weekly dose of both moxifloxacin and 1200 mg of rifapentine for 4 months. Sputum specimens were examined on microscopy and after culture at regular intervals. The primary end point was a composite treatment failure and relapse, with noninferiority based on a margin of 6 percentage points and 90% confidence intervals. Results We enrolled a total of 827 patients from South Africa, Zimbabwe, Botswana, and Zambia; 28% of patients were coinfected with the human immunodefiency virus. In the per-protocol analysis, the proportion of patients with an unfavorable response was 4.9% in the control group, 3.2% in the 6-month group (adjusted difference from control, -1.8 percentage points; 90% confidence interval [CI], -6.1 to 2.4), and 18.2% in the 4-month group (adjusted difference from control, 13.6 percentage points; 90% CI, 8.1 to 19.1). In the modified intention-to-treat analysis these proportions were 14.4% in the control group, 13.7% in the 6-month group (adjusted difference from control, 0.4 percentage points; 90% CI, -4.7 to 5.6), and 26.9% in the 4-month group (adjusted difference from control, 13.1 percentage points; 90% CI, 6.8 to 19.4). Conclusions The 6-month regimen that included weekly administration of high-dose rifapentine and moxifloxacin was as effective as the control regimen. The 4-month regimen was not noninferior to the control regimen. (Funded by the European and Developing Countries Clinical Trials Partnership and the Wellcome Trust; RIFAQUIN Current Controlled Trials number, ISRCTN44153044 .).

Concepts: The Canon of Medicine, Normal distribution, Clinical trial, Interval estimation, Confidence interval, Rifampicin, Tuberculosis treatment, Tuberculosis


The objectives of this study were to investigate the effect of grapefruit juice low in furanocoumarins on CYP3A activity and to summarize previous findings of enzyme inhibition measured by the metabolism of midazolam after intake of grapefruit juice. Twelve healthy volunteers participated in a prospective, randomized, double-blinded, three-way crossover clinical study to determine the effect of regular grapefruit juice (RGJ) and a novel, low furanocoumarin hybrid grapefruit juice (HGJ) on the metabolism of oral midazolam, used as a probe for in vivo CYP3A activity, compared with water as a control. The RGJ was 100% hand-squeezed Hudson grapefruit juice, and the HGJ contained low amounts of furanocoumarin constituents. The point estimates (90% confidence intervals) for the RGJ/water midazolam AUC geometric mean ratio was 122% (107 - 140). The point estimate for the HGJ/water midazolam AUC ratio was within the 80%-125% bioequivalence range, indicating an absence of interaction. This finding also prompted a systematic review of available evidence on the pharmacokinetic alteration of midazolam by grapefruit juice. While most studies demonstrated alteration in midazolam pharmacokinetics supporting inhibition of CYP3A activity as a likely mechanism, the cohorts included in these studies and the extent of the pharmacokinetic interaction varied widely. The current study indicated grapefruit juice-drug interaction varies substantially based on patient characteristics and/or grapefruit juice product-related factors, including the amount of furanocoumarin constituents present in the juice. This article is protected by copyright. All rights reserved.

Concepts: Interval estimation, Estimator, Copyright, Clinical research, Enzyme inhibitor, Midazolam, Bioavailability, Pharmacology


Purpose To determine if a reduced-dose computed tomography (CT) protocol could effectively help to identify patients in the emergency department (ED) with moderate to high likelihood of calculi who would require urologic intervention within 90 days. Materials and Methods The study was approved by the institutional review board and written informed consent with HIPAA authorization was obtained. This was a prospective, single-center study of patients in the ED with moderate to high likelihood of ureteral stone undergoing CT imaging. Objective likelihood of ureteral stone was determined by using the previously derived and validated STONE clinical prediction rule, which includes five elements: sex, timing, origin, nausea, and erythrocytes. All patients with high STONE score (STONE score, 10-13) underwent reduced-dose CT, while those with moderate likelihood of ureteral stone (moderate STONE score, 6-9) underwent reduced-dose CT or standard CT based on clinician discretion. Patients were followed to 90 days after initial imaging for clinical course and for the primary outcome of any intervention. Statistics are primarily descriptive and are reported as percentages, sensitivities, and specificities with 95% confidence intervals. Results There were 264 participants enrolled and 165 reduced-dose CTs performed; of these participants, 108 underwent reduced-dose CT alone with complete follow-up. Overall, 46 of 264 (17.4%) of patients underwent urologic intervention, and 25 of 108 (23.1%) patients who underwent reduced-dose CT underwent a urologic intervention; all were correctly diagnosed on the clinical report of the reduced-dose CT (sensitivity, 100%; 95% confidence interval: 86.7%, 100%). The average dose-length product for all standard-dose CTs was 857 mGy · cm ± 395 compared with 101 mGy · cm ± 39 for all reduced-dose CTs (average dose reduction, 88.2%). There were five interventions for nonurologic causes, three of which were urgent and none of which were missed when reduced-dose CT was performed. Conclusion A CT protocol with over 85% dose reduction can be used in patients with moderate to high likelihood of ureteral stone to safely and effectively identify patients in the ED who will require urologic intervention. (©) RSNA, 2016 Online supplemental material is available for this article.

Concepts: Normal distribution, Prediction interval, Interval estimation, Clinical trial, Clinical prediction rule, Confidence interval, Nuisance parameter, Informed consent


Computational chemistry is a largely empirical field that makes predictions with substantial uncertainty. And yet the use of standard statistical methods to quantify this uncertainty is often absent from published reports. This article covers the basics of confidence interval estimation for molecular modeling using classical statistics. Alternate approaches such as non-parametric statistics and bootstrapping are discussed.

Concepts: Resampling, Interval estimation, Normal distribution, Mathematics, Statistical hypothesis testing, Statistical inference, Statistics, Confidence interval