Current regulatory guidance and practice of non-inferiority trials are asymmetric in favor of the test treatment (Test) over the reference treatment (Control). These trials are designed to compare ...the relative efficacy of Test to Control by reference to a clinically important margin, M.
Non-inferiority trials allow for the conclusion of: (a) non-inferiority of Test to Control if Test is slightly worse than Control but by no more than M; and (b) superiority if Test is slightly better than Control even if it is by less than M. From Control's perspective, (b) should lead to a conclusion of non-inferiority of Control to Test. The logical interpretation ought to be that, while Test is statistically better, it is not clinically superior to Control (since Control should be able to claim non-inferiority to Test). This article makes a distinction between statistical and clinical significance, providing for symmetry in the interpretation of results. Statistical superiority and clinical superiority are achieved, respectively, when the null and the non-inferiority margins are exceeded. We discuss a similar modification to placebo-controlled trials.
Rules for interpretation should not favor one treatment over another. Claims of statistical or clinical superiority should depend on whether or not the null margin or the clinically relevant margin is exceeded.
Abstract Background Docosahexaenoic acid (DHA) plays an important role in neural function. Decreases in plasma DHA are associated with cognitive decline in healthy elderly adults and in patients with ...Alzheimer's disease. Higher DHA intake is inversely correlated with relative risk of Alzheimer's disease. The potential benefits of DHA supplementation in age-related cognitive decline (ARCD) have not been fully examined. Objective Determine effects of DHA administration on improving cognitive functions in healthy older adults with ARCD. Methods Randomized, double-blind, placebo-controlled, clinical study was conducted at 19 U.S. clinical sites. A total of 485 healthy subjects, aged ≥55 with Mini-Mental State Examination >26 and a Logical Memory (Wechsler Memory Scale III) baseline score ≥1 standard deviation below younger adults, were randomly assigned to 900 mg/d of DHA orally or matching placebo for 24 weeks. The primary outcome was the CANTAB Paired Associate Learning (PAL), a visuospatial learning and episodic memory test. Results Intention-to-treat analysis demonstrated significantly fewer PAL six pattern errors with DHA versus placebo at 24 weeks (difference score, −1.63 ± 0.76 −3.1, −0.14, 95% CI, P = .03). DHA supplementation was also associated with improved immediate and delayed Verbal Recognition Memory scores ( P < .02), but not working memory or executive function tests. Plasma DHA levels doubled and correlated with improved PAL scores ( P < .02) in the DHA group. DHA was well tolerated with no reported treatment-related serious adverse events. Conclusions Twenty-four week supplementation with 900 mg/d DHA improved learning and memory function in ARCD and is a beneficial supplement that supports cognitive health with aging. Trial Registration Clinicaltrials.gov , Identifier: NCT0027813.
We propose a simple modification of Hochberg's step‐up Bonferroni procedure for multiple tests of significance. The proposed procedure is always more powerful than Hochberg's procedure for more than ...two tests, and is more powerful than Hommel's procedure for three and four tests. A numerical analysis of the new procedure indicates that its Type I error is controlled under independence of the test statistics, at a level equal to or just below the nominal Type I error. Examination of various non‐null configurations of hypotheses shows that the modified procedure has a power advantage over Hochberg's procedure which increases in relationship to the number of false hypotheses.
Group sequential clinical trial designs allow the sequential hypothesis testing as data is accumulated over time, while ensuring the control of type-1 error rate. These designs vary in how they split ...the overall type-1 error among analyses, but practically, all assume that: 1. The underlying data is normal or approximately so, and 2. the sample sizes are large, so the individual test statistics are sufficiently normal rather than Student's t. These two assumptions lead to the reliance on the multivariate normal distribution for calculation of the critical values. Several publications have pointed out that for small sample sizes, such an approach leads to an inflated type-1 error and proposed different sets of critical values from either simulations or by an ad-hoc adjustment to the asymptotic critical values. In this paper, we develop the exact joint distribution of the test statistics for any sample size. We show how to calculate exact critical values that conform to some well-known alpha-spending functions, such as the O'Brien-Fleming and Pocock critical values. We also compare the resulting type-1 error of these critical values with the asymptotic, as well as with other methods that have been proposed for small sample sizes.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, GIS, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Culture and assessment of manic symptoms Mackin, Paul; Targum, Steven D.; Kalali, Amir ...
British journal of psychiatry,
10/2006, Letnik:
189, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Cultural background may influence the perception of psychiatric symptoms. We examined the effects of cultural biases on the identification of manic symptoms using the Young Mania Rating Scale. Two ...video interviews, each with an American person with mania, were shown to psychiatrists from three countries (US, UK and India). Total scores on the scale differed significantly between the US and UK (P < 0.001) and between India and UK (P < 0.001) rater groups. Overall, differences between India and US rater groups were less marked (P=0.28). These differences suggest that cultural biases influence the interpretation of manic symptoms.
We introduce an improved Bonferroni method for testing two primary endpoints in clinical trial settings using a new data-adaptive critical value that explicitly incorporates the sample correlation ...coefficient. Our methodology is developed for the usual Student's t-test statistics for testing the means under normal distributional setting with unknown population correlation and variances. Specifically, we construct a confidence interval for the unknown population correlation and show that the estimated type-1 error rate of the Bonferroni method with the population correlation being estimated by its lower confidence limit can be bounded from above less conservatively than using the traditional Bonferroni upper bound. We also compare the new procedure with other procedures commonly used for the multiple testing problem addressed in this paper.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, GIS, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Reliable clinical assessment tools are needed to evaluate the effects of injectable devices and fillers. This study was designed to validate a new photonumeric wrinkle assessment scale using ...standardized photographic methodology to obtain reference photographs.
Multiple photographs (test set) from approximately 78 volunteer subjects with varying degrees of severity of the left/right nasolabial fold wrinkles were examined. Photographs of 18 subjects representing the full spectrum of nasolabial fold wrinkle severity were selected from the test set by a study team of three independent physicians and were classified using a six-point scale (0 = no wrinkles; 5 = very deep wrinkle, redundant fold). One representative photograph was identified by study team consensus for each of the six scale points. Photographs were randomly arranged in booklets for a second, independent, group of five physician raters to grade both left/right nasolabial fold wrinkles twice over a 2-week interval. The scale was considered valid if interevaluator reliability, as measured by intraclass correlation coefficient, was greater than or equal to 80 percent.
Intrarater reliability was significant (p < 0.001) for all five physicians and overall, with Pearson correlation coefficients greater than 92 percent in all cases. The overall weighted kappa coefficient for intrarater reliability for all five raters was 0.598 (range, 0.433 to 0.684). The overall interrater reliability kappa value was 0.525, and a high degree of interrater reliability was observed at week 1 and week 2 time points (intraclass correlation coefficient = 0.890 and 0.880, p < 0.001 for both), validating the new wrinkle assessment scale.
This study validates the new wrinkle assessment scale, which provides a reliable clinical tool for use in nasolabial fold wrinkle evaluation.
Summary
Introduction
Acne is a common, chronic skin disease that has both physical and psychological consequences. Over‐the‐counter products are a treatment option frequently chosen by dermatologists ...and acne sufferers for reasons of cost or convenience. There are reports that such products can effect rapid resolution in certain lesion parameters.
Aims
To evaluate the short‐term effect of a benzoyl peroxide 3% gel on acne lesions.
Methods
A 5‐day, double‐blind, randomized clinical trial was conducted among subjects with mild‐to‐moderate acne. Subjects applied the benzoyl peroxide 3% gel, a salicylic acid 2% gel, or a vehicle gel under supervision once daily for 4 days. Target lesion parameters of swelling, diameter, and erythema were evaluated at various times after the first and subsequent applications.
Results
Although target lesion parameters showed overall improvement from baseline, the effects of the active treatment gels were not significantly different from those of the vehicle gel at any evaluation. The assessed parameters showed marked variability in target lesion behavior at the subject level over the course of the study.
Conclusions
The results of this study illustrate the unpredictability of individual acne lesion's responses to therapy and the challenge associated with using these responses to judge short‐term treatment efficacy. While rapid acne resolution is desired by patients and consumers, setting realistic expectations for treatment response is critical to encourage compliance and avoid disappointment.
In this paper we derive a new p-value based multiple testing procedure that improves upon the Hommel procedure by gaining power as well as having a simpler step-up structure similar to the Hochberg ...procedure. The key to this improvement is that the Hommel procedure can be improved by a consonant procedure. Exact critical constants of this new procedure can be numerically determined. The zeroth-order approximations to the exact critical constants, albeit slightly conservative, are simple to use and need no tabling, and hence are recommended in practice. The proposed procedure is shown to control the familywise error rate under independence among the p-values. Simulations empirically demonstrate familywise error rate control under positive and negative dependence. Power superiority of the proposed procedure over competing ones is also empirically demonstrated. Illustrative examples are given.
Docosahexaenoic acid (DHA), a long-chain omega-3 fatty acid, is important for eye and brain development and ongoing visual, cognitive, and cardiovascular health. Unlike fish-sourced oils, the ...bioavailability of DHA from vegetarian-sourced (algal) oils has not been formally assessed. We assessed bioequivalence of DHA oils in capsules from two different algal strains versus bioavailability from an algal-DHA-fortified food. Our 28-day randomized, placebo-controlled, parallel group study compared bioavailability of (a) two different algal DHA oils in capsules (“DHASCO-T” and “DHASCO-S”) at doses of 200, 600, and 1,000 mg DHA per day (n = 12 per group) and of (b) an algal-DHA-fortified food (n = 12). Bioequivalence was based on changes in plasma phospholipid and erythrocyte DHA levels. Effects on arachidonic acid (ARA), docosapentaenoic acid-n-6 (DPAn-6), and eicosapentaenoic acid (EPA) were also determined. Both DHASCO-T and DHASCO-S capsules produced equivalent DHA levels in plasma phospholipids and erythrocytes. DHA response was dose-dependent and linear over the dose range, plasma phospholipid DHA increased by 1.17, 2.28 and 3.03 g per 100 g fatty acid at 200, 600, and 1,000 mg dose, respectively. Snack bars fortified with DHASCO-S oil also delivered equivalent amounts of DHA on a DHA dose basis. Adverse event monitoring revealed an excellent safety and tolerability profile. Two different algal oil capsule supplements and an algal oil-fortified food represent bioequivalent and safe sources of DHA.
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