Step‐down multiple tests for comparing treatments with a control in unbalanced one‐way layouts

Dunnett, Charles W.; Tamhane, Ajit C.

doi:10.1002/sim.4780100614

Cited by 141 publications

(95 citation statements)

References 13 publications

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“…To adjust for multiple comparisons, the step-down multiple testing framework for comparing treatments with a control of Dunnet and Tamhane was used. 22 For the primary efficacy measure, the two-sided significance level was 0.05. The primary efficacy end point was analysed using analysis of covariance (ANCOVA) with treatment, centre, and treatment-by-centre as factors.…”

Section: Mitt Populationmentioning

confidence: 99%

A randomized double-blind placebo-controlled study of the long-term efficacy and safety of topiramate in the treatment of obese subjects

et al. 2004

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BACKGROUND: Treatment of obese subjects with topiramate has recently been associated with significant weight loss in a 6-month dose-ranging study. OBJECTIVE: To investigate the long-term efficacy and safety of topiramate in obese subjects. DESIGN: Randomised, double-blind, placebo-controlled study investigating three doses of topiramate: 96, 192, and 256 mg/ day. All subjects also participated in a nonpharmacological weight-loss programme. SUBJECTS: The study included 1289 subjects 18-75 y with a body mass index Z30 kg/m 2 and o50 kg/m 2 in the absence of comorbidities, or Z27 kg/m 2 and o50 kg/m 2 in the presence of controlled hypertension and/or dyslipidaemia. DURATION: The original study design was for a 6-week, single-blind, placebo run-in phase followed by an 8-week titration phase and 2 y of maintenance at the assigned dose. Sponsor ended study early in order to develop a new controlled-release formulation with the potential to enhance tolerability and simplify dosing in this patient population. Therefore, none of the subjects completed the full 2 y of treatment. Efficacy results are based on subjects who were enrolled early enough to have had an opportunity to complete 1 y at their assigned dose (modified intent-to-treat population, MITT) before learning of the decision to terminate the study. Safety results are based on all subjects who took at least one dose of study medication. RESULTS: The safety population consisted of 1282 subjects, and the MITT efficacy population was 854 subjects. At 60 weeks, subjects in the placebo group lost 1.7% of their baseline body weight, while subjects in the topiramate 96, 192, and 256 mg/day treatment groups lost 7.0, 9.1, and 9.7%, respectively (Po0.001, MITT, last observation carried forward). Weight loss Z5% of baseline weight was achieved by 18% of subjects in the placebo arm vs 54, 61, and 67% of subjects receiving topiramate 96, 192, and 256 mg/day, respectively; weight loss Z10% was achieved by 6 vs 29, 40, and 44%, respectively (Po0.001). Weight loss was accompanied by significant improvements in blood pressure (systolic/diastolic changes of þ 0.4/ þ 1.0, À3.1/À1.3, À5.7/À3.4, and À4.6/À2.4 mmHg were observed for placebo, topiramate 96 mg/day, 192 mg/day, and 256 mg/day, respectively, Po0.001) and glucose and insulin. The most common adverse events more frequently observed in topiramatetreated subjects occurred mostly during the titration phase and were related to the central or peripheral nervous system and included paresthesia, difficulty with concentration/attention, depression, difficulty with memory, language problems, nervousness, and psychomotor slowing. CONCLUSION: Topiramate treatment of obese subjects over the course of 1 y resulted in clinically significant weight loss. Improvements were also observed in blood pressure and glucose tolerance.

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Section: Mitt Populationmentioning

confidence: 99%

A randomized double-blind placebo-controlled study of the long-term efficacy and safety of topiramate in the treatment of obese subjects

et al. 2004

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“…Statistical analysis of results was performed by employing a factorial analysis of variance (ANOVA), or by a one-way ANOVA, followed by a Tukey-Cramer’s multiple comparison test of a Dunnett’s t test [30]. General rhythmic parameters such as acrophase (the maximum of the sinus function fit by the experimental data), mesor (the statistical estimate of the mean) and amplitude (half the difference between calculated maximal and minimal values) were calculated by Cosinor analysis.…”

Section: Methodsmentioning

confidence: 99%

Effect of Melatonin on 24-Hour Rhythms of Ornithine Decarboxylase Activity and Norepinephrine and Acetylcholine Synthesis in Submaxillary Lymph Nodes and Spleen of Young and Aged Rats

Cardinali

Garcı́a-Bonacho²,

Esquifino³

1998

Neuroendocrinology

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Young (50 days old) and old (18 months old) Sprague-Dawley rats were injected with mycobacterial Freund’s adjuvant to produce an inflammatory disease of the joints and were studied the day before, and on days 6, 12 and 18 after injection. At every postinjection interval examined, old rats had significantly lower circadian amplitudes of pineal melatonin content. On day 18 of arthritis development, decreased levels of pineal melatonin were also seen in young rats. A second study, carried out 18 days after the injection of Freund’s complete adjuvant and after 17 daily injections of 10 or 100 µg of melatonin in the evening, indicated that melatonin treatment restored the inflammatory response in old rats (assessed plethysmographically in hind paws) to the level found in young animals. In young rats, an inflammation-promoting effect of 100 µg melatonin could be demonstrated. As a consequence of the immune reaction, submaxillary lymph node and splenic ornithine decarboxylase activity (an index of lymph cell proliferation) augmented significantly, with acrophases of 24-hour rhythms in the afternoon for lymph nodes or in the morning for spleen. Mesor and amplitude of ornithine decarboxylase rhythm were lowest in old rats, while melatonin injection generally augmented its amplitude. Lymph node and splenic tyrosine hydroxylase activity (a presynaptic adrenergic marker) reached maximal values during early night hours while maximal values of [³H]acetylcholine synthesis (a presynaptic cholinergic marker) occurred during the afternoon in lymph nodes. Amplitude and mesor of these rhythms were lowest in old rats, an effect generally counteracted by melatonin treatment. The results suggest that inflammation is accompanied by an age-dependent, significant depression of pineal melatonin synthesis during adjuvant-induced arthritis and a decreased amplitude of the circadian rhythm of immune cell proliferation and autonomic activity in lymph nodes and spleen. These effects are counteracted by injection of melatonin, mainly in old rats.

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“…Step-down procedures in multiple testing offer a more powerful approach than single-step procedures and come in two flavors, step-up and step-down (34,35).…”

Section: Resultsmentioning

confidence: 99%

Second-generation high-throughput forward genetic screen in mice to isolate subtle behavioral mutants

Kumar

Kim

Joseph

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Forward genetic screens have been highly successful in revealing roles of genes and pathways in complex biological events. Traditionally these screens have focused on isolating mutants with the greatest phenotypic deviance, with the hopes of discovering genes that are central to the biological event being investigated. Behavioral screens in mice typically use simple activity-based assays as endophenotypes for more complex emotional states of the animal. They generally set the selection threshold for a putative mutant at 3 SDs (z score of 3) from the average behavior of normal animals to minimize false-positive results. Behavioral screens using a high threshold for detection have generally had limited success, with high false-positive rates and subtle phenotypic differences that have made mapping and cloning difficult. In addition, targeted reverse genetic approaches have shown that when genes central to behaviors such as open field behavior, psychostimulant response, and learning and memory tasks are mutated, they produce subtle phenotypes that differ from wild-type animals by 1 to 2 SDs (z scores of 1 to 2). We have conducted a second-generation (G2) dominant Nethyl-N-nitrosourea (ENU) screen especially designed to detect subtle behavioral mutants for open field activity and psychostimulant response behaviors. We successfully detect mutant lines with only 1 to 2 SD shifts in mean response compared with wild-type control animals and present a robust statistical and methodological framework for conducting such forward genetic screens. Using this methodology we have screened 229 ENU mutant lines and have identified 15 heritable mutant lines. We conclude that for screens in mice that use activity-based endophenotypic measurements for complex behavioral states, this G2 screening approach yields better results.

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Step‐down multiple tests for comparing treatments with a control in unbalanced one‐way layouts

Cited by 141 publications

References 13 publications

A randomized double-blind placebo-controlled study of the long-term efficacy and safety of topiramate in the treatment of obese subjects

A randomized double-blind placebo-controlled study of the long-term efficacy and safety of topiramate in the treatment of obese subjects

Effect of Melatonin on 24-Hour Rhythms of Ornithine Decarboxylase Activity and Norepinephrine and Acetylcholine Synthesis in Submaxillary Lymph Nodes and Spleen of Young and Aged Rats

Second-generation high-throughput forward genetic screen in mice to isolate subtle behavioral mutants

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