Random Guess and Wishful Thinking are the Best Blinding Scenarios.

Blinding is a methodologic safeguard of treatment evaluation, yet severely understudied empirically. Mathieu et al.'s theoretical analysis (2014) provided an important message that blinding cannot eliminate potential for bias associated with belief about allocation in randomized controlled trial; just like the intent-to-treat principle does not guarantee unbiased estimation under noncompliance, the blinded randomized trial as a golden standard may produce bias. They showed possible biases but did not assess how large the bias could be in different scenarios. In this paper, we examined their findings, and numerically assessed and compared the bias in treatment effect parameters by simulation under frequently encountered blinding scenarios, aiming to identify the most ideal blinding scenarios in practice. We conclude that Random Guess and Wishful Thinking (e.g., participants tend to believe they received treatment) are the most ideal blinding scenarios, incurring minimal bias. We also find some evidence that imperfect or partial blinding can be better than no blinding

Tutorial in biostatistics: Analyzing associations between total plasma homocysteine and B vitamins using optimal categorization and segmented regression

Data analysts consider standard regression models (e.g., generalized linear model) or nonparametric smoothing techniques (e.g., loess or splines) when examining the association between two variables. Before this step, a quantile-based summarization is typically used for exploring the exposure-response relationship. Unfortunately, these exploratory approaches may not be optimal or efficient for guiding the formal analysis in many biological and nutritional data settings. We suggest a recently developed method for selection of cutpoints as a tool of data summary and segmented regression as a modeling approach in the analysis of plasma total homocysteine and related vitamins. These methods are often complementary in discovering the underlying complex pattern of association. Copyright © 2006 S. Karger AG

Ten-Year Anniversary of Brownfields Legislation

OBJECTIVE:We hypothesized (1) that gastrointestinal (GI) and renal adverse events (AE) would occur more often in infants first prescribed ibuprofen before rather than after six months of age and (2) that ibuprofen would be associated with more adverse effects than acetaminophen in infants younger than six months. METHODS:We created two partly overlapping retrospective cohorts of infants aged less than six months when California Medicaid first paid for ibuprofen or acetaminophen between 2004 and 2010. In the first cohort we compared the incidence rate ratio (RR) of GI and renal AE between those infants first prescribed ibuprofen before six months of age with those first prescribed ibuprofen after six months of age. In the second cohort we compared the RR of GI and renal AE between infants younger than six months prescribed ibuprofen (+/-acetaminophen) with those prescribed only acetaminophen. RESULTS:We identified 41,669 prescriptions for ibuprofen and 176,991 prescriptions for acetaminophen in 180,333 eligible infants (median age 2.1 months). We did not observe higher RR of any AE in infants first prescribed ibuprofen before rather than after six months of age. Most infants prescribed ibuprofen were also prescribed acetaminophen. Any GI (adjusted (a)RR 1.25, 95% CI 1.13-1.38) and moderate or severe GI AE (aRR 1.24, 95% CI 1.09-1.40) were more common in infants younger than six months who were prescribed ibuprofen versus acetaminophen alone. Severe GI (aRR 0.63, 95% CI 0.27-1.45) and renal AE (aRR 1.84 95% CI 0.66-5.19) were not different between the ibuprofen (+/-acetaminophen) and acetaminophen-only groups. CONCLUSIONS:GI and renal AEs were not higher in infants younger than six months who were prescribed ibuprofen compared with those aged six to 12 months. AEs were increased in infants younger than six months who were prescribed ibuprofen compared with infants who were prescribed acetaminophen alone

Effect of renal impairment on atherosclerosis: Only partially mediated by homocysteine

Background Cardiovascular risk and plasma total homocysteine (tHcy) are high in patients with renal failure. High tHcy may account for a substantial part of the increased risk. We assessed mediation by tHcy of the association of estimated glomerular filtration rate (eGFR CKD/EPI) with carotid total plaque area (TPA) and carotid stenosis. Methods TPA and carotid stenosis were measured by ultrasound. Multiple linear regression was used to assess the effects of eGFR and/or tHcy after adjustment for age, sex, systolic blood pressure (SBP), smoking, LDL, HDL and weight. Results Complete data were available for 1967 patients. eGFR decreased, and TPA and total stenosis increased linearly with age. After adjustment [age, sex, SBP, smoking (in pack years), low-density lipoprotein (LDL), high-density lipoprotein (HDL) and weight], eGFR and tHcy were independently associated with TPA (P \u3c 0.01), but when both were added to the model, their significance was attenuated (P = 0.06 for eGFR, 0.03 for tHcy). Mediation analysis showed that tHcy seems to contribute to a significant mediation of the association of eGFR with TPA but not stenosis; after adjustment for the set of risk factors listed above, tHcy still demonstrated significant mediation on TPA (P = 0.03), but not on stenosis (P = 0.16). Conclusions tHcy accounts for a significant part, but not all of the effect of renal impairment on atherosclerosis. Other uremic toxins including metabolic products of the intestinal microbiome may explain residual effects of renal failure on atherosclerosis. Therapeutic approaches arising from that hypothesis are discussed

Rapid Multiplex Testing for Upper Respiratory Pathogens in the Emergency Department: A Randomized Controlled Trial.

Background:Acute upper respiratory tract infections are a common cause of emergency department (ED) visits and often result in unnecessary antibiotic treatment. Methods:We conducted a randomized clinical trial to evaluate the impact of a rapid, multipathogen respiratory panel (RP) test vs usual care (control). Patients were eligible if they were ≥12 months old, had symptoms of upper respiratory infection or influenza-like illness, and were not on antibiotics. The primary outcome was antibiotic prescription; secondary outcomes included antiviral prescription, disposition, and length of stay (ClinicalTrials.gov# NCT02957136). Results:Of 191 patients enrolled, 93 (49%) received RP testing; 98 (51%) received usual care. Fifty-three (57%) RP and 7 (7%) control patients had a virus detected and reported during the ED visit (P = .0001). Twenty (22%) RP patients and 33 (34%) usual care patients received antibiotics during the ED visit (-12%; 95% confidence interval, -25% to 0.4%; P = .06/0.08); 9 RP patients received antibiotics despite having a virus detected. The magnitude of antibiotic reduction was greater in children (-19%) vs adults (-9%, post hoc analysis). There was no difference in antiviral use, length of stay, or disposition. Conclusions:Rapid RP testing was associated with a trend toward decreased antibiotic use, suggesting a potential benefit from more rapid viral tests in the ED. Future studies should determine if specific groups are more likely to benefit from testing and evaluate the relative cost and effectiveness of broad testing, focused testing, and a combined diagnostic and antimicrobial stewardship approach

Towards a proposal for assessment of blinding success in clinical trials: up-to-date review

The CONSORT statement recommended that investigators should clearly report which key trial persons were blinded to treatment allocation and test for the success of blinding. Clinical researchers, however, more often than not overlook the assessment of the success of blinding. The severe under-reporting on the success of blinding may improve with awareness of existing quantitative methods. The two statistical methods, James' blinding index (BI) and Bang's BI, are currently available. Subjects could be asked to guess their treatment assignment, possibly with an option to express the degree of certainty. Assessments of blinding at various points may serve different purposes, i.e. to evaluate comparability between experimental versus control treatments before the trial by the third party; to examine further comparability and credibility of the control treatment and patients' expectation about treatment received in early stage of the trial, and to summarize the overall maintenance of the blinding success at the end of the trial. In this article, we review BIs and how to use these methods along with discussion of other issues in blinding assessment and reporting. We contend the two BIs that were independently developed but carry complementary properties would characterize blinding behaviours in clinical trials qualitatively as well as quantitatively, and may also shed some lights on the interpretation of the study findings. Finally we urge the Item 11b of the CONSORT statement to be revised to require the assessment/reporting of blinding success for all trials that adopt blinding schemes

Vitamin intervention for stroke prevention trial: An efficacy analysis

Background and Purpose - The Vitamin Intervention for Stroke Prevention trial (VISP) intention-to-treat analysis did not show efficacy of combined vitamin therapy for recurrent vascular events in patients with nondisabling stroke. Reasons for lack of efficacy may have included folate fortification of grain products, inclusion of the recommended daily intake for B12 in the low-dose arm, treatment with parenteral B12 in patients with low B12 levels in both study arms, a dose of B12 too low for patients with malabsorption, supplementation with nonstudy vitamins, and failure of patients with significant renal impairment to respond to vitamin therapy. We conducted an efficacy analysis limited to patients most likely to benefit from the treatment, based on hypotheses arising from evidence developed since VISP was initiated. The criteria for this subgroup were defined before any data analysis. Methods - For this analysis, we excluded patients with low and very high B12 levels at baseline (\u3c250 and \u3e637 pmol/L, representing the 25th and 95th percentiles), to exclude those likely to have B12 malabsorption or to be taking B12 supplements outside the study and patients with significant renal impairment (glomerular filtration rate \u3c46.18; the 10th percentile). Results - This subgroup represents 2155 patients (37% female), with a mean age of 66±10.7 years. For the combined end point of ischemic stroke, coronary disease, or death, there was a 21% reduction in the risk of events in the high-dose group compared with the low-dose group (unadjusted P=0.049; adjusted for age, sex, blood pressure, smoking, and B12 level P=0.056). In Kaplan-Meier survival analysis comparing 4 groups, patients with a baseline B12 level at the median or higher randomized to high-dose vitamin had the best overall outcome, and those with B12 less than the median assigned to low-dose vitamin had the worst (P=0.02 for combined stroke, death, and coronary events; P=0.03 for stroke and coronary events). Conclusions - In the era of folate fortification, B12 plays a key role in vitamin therapy for total homocysteine. Higher doses of B12, and other treatments to lower total homocysteine may be needed for some patients. © 2005 American Heart Association, Inc

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Blinding Measured: A Systematic Review of Randomized Controlled Trials of Acupuncture

Background. There is no agreement among researchers on viable controls for acupuncture treatment, and the assessment of the effectiveness of blinding and its interpretation is rare. Purpose. To systematically assess the effectiveness of blinding (EOB) in reported acupuncture trials; to explore results of RCTs using a quantitative measure of EOB. Data Sources. A systematic review of published sham RCTs that assessed blinding. Study Selection. Five hundred and ninety studies were reviewed, and 54 studies (4783 subjects) were included. Data Extraction. The number of patients who guessed their treatment identity was extracted from each study. Variables with possible influence on blinding were identified. Data Synthesis. The blinding index was calculated for each study. Based on blinding indexes, studies were congregated into one of the nine blinding scenarios. Individual study characteristics were explored for potential association with EOB. Limitations. There is a possibility of publication or reporting bias. Conclusions. The most common scenario was that the subjects believed they received verum acupuncture regardless of the actual treatment received, and overall the subject blinding in the acupuncture studies was satisfactory, with 61% of study participants maintaining ideal blinding. Objectively calculated blinding data may offer meaningful and systematic ways to further interpret the findings of RCTs