Type I error rates of multi-arm multi-stage clinical trials: strong control and impact of intermediate outcomes

BACKGROUND: The multi-arm multi-stage (MAMS) design described by Royston et al. [Stat Med. 2003;22(14):2239-56 and Trials. 2011;12:81] can accelerate treatment evaluation by comparing multiple treatments with a control in a single trial and stopping recruitment to arms not showing sufficient promise during the course of the study. To increase efficiency further, interim assessments can be based on an intermediate outcome (I) that is observed earlier than the definitive outcome (D) of the study. Two measures of type I error rate are often of interest in a MAMS trial. Pairwise type I error rate (PWER) is the probability of recommending an ineffective treatment at the end of the study regardless of other experimental arms in the trial. Familywise type I error rate (FWER) is the probability of recommending at least one ineffective treatment and is often of greater interest in a study with more than one experimental arm. METHODS: We demonstrate how to calculate the PWER and FWER when the I and D outcomes in a MAMS design differ. We explore how each measure varies with respect to the underlying treatment effect on I and show how to control the type I error rate under any scenario. We conclude by applying the methods to estimate the maximum type I error rate of an ongoing MAMS study and show how the design might have looked had it controlled the FWER under any scenario. RESULTS: The PWER and FWER converge to their maximum values as the effectiveness of the experimental arms on I increases. We show that both measures can be controlled under any scenario by setting the pairwise significance level in the final stage of the study to the target level. In an example, controlling the FWER is shown to increase considerably the size of the trial although it remains substantially more efficient than evaluating each new treatment in separate trials. CONCLUSIONS: The proposed methods allow the PWER and FWER to be controlled in various MAMS designs, potentially increasing the uptake of the MAMS design in practice. The methods are also applicable in cases where the I and D outcomes are identical

Frequent Arousal from Hibernation Linked to Severity of Infection and Mortality in Bats with White-Nose Syndrome

White-nose syndrome (WNS), an emerging infectious disease that has killed over 5.5 million hibernating bats, is named for the causative agent, a white fungus (Geomyces destructans (Gd)) that invades the skin of torpid bats. During hibernation, arousals to warm (euthermic) body temperatures are normal but deplete fat stores. Temperature-sensitive dataloggers were attached to the backs of 504 free-ranging little brown bats (Myotis lucifugus) in hibernacula located throughout the northeastern USA. Dataloggers were retrieved at the end of the hibernation season and complete profiles of skin temperature data were available from 83 bats, which were categorized as: (1) unaffected, (2) WNS-affected but alive at time of datalogger removal, or (3) WNS-affected but found dead at time of datalogger removal. Histological confirmation of WNS severity (as indexed by degree of fungal infection) as well as confirmation of presence/absence of DNA from Gd by PCR was determined for 26 animals. We demonstrated that WNS-affected bats aroused to euthermic body temperatures more frequently than unaffected bats, likely contributing to subsequent mortality. Within the subset of WNS-affected bats that were found dead at the time of datalogger removal, the number of arousal bouts since datalogger attachment significantly predicted date of death. Additionally, the severity of cutaneous Gd infection correlated with the number of arousal episodes from torpor during hibernation. Thus, increased frequency of arousal from torpor likely contributes to WNS-associated mortality, but the question of how Gd infection induces increased arousals remains unanswered

Direct comparison of the FibroScan XL and M probes for assessment of liver fibrosis in obese and nonobese patients

Esteban Durango,1,* Christian Dietrich,1,* Helmut Karl Seitz,1 Cornelia Ursula Kunz,2 Gilles T Pomier-Layrargues,3 Andres Duarte-Rojo,4 Melanie Beaton,5 Magdy Elkhashab,6 Robert P Myers,7 Sebastian Mueller1,3 1Department of Medicine and Center for Alcohol Research, Liver Disease and Nutrition, Salem Medical Center, 2Institute of Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany; 3Liver Unit, Centre Hospitalier de l&#39;Universit&eacute; de Montr&eacute;al, H&ocirc;pital Saint-Luc, Montr&eacute;al, Quebec, 4Toronto Western Hospital Liver Centre, Toronto, Ontario; 5Multi-Organ Transplant Unit, University of Western Ontario, London, Ontario; 6The Toronto Liver Centre, Toronto, Ontario; 7Liver Unit, Division of Gastroenterology and Hepatology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada *These authors contributed equally to this researchBackground: A novel Fibroscan XL probe has recently been introduced and validated for obese patients, and has a diagnostic accuracy comparable with that of the standard M probe. The aim of this study was to analyze and understand the differences between these two probes in nonobese patients, to identify underlying causes for these differences, and to develop a practical algorithm to translate results for the XL probe to those for the M probe.Methods and results: Both probes were directly compared first in copolymer phantoms of varying stiffness (4.8, 11, and 40 kPa) and then in 371 obese and nonobese patients (body mass index, range 17.2&ndash;72.4) from German (n = 129) and Canadian (n = 242) centers. Liver stiffness values for both probes correlated better in phantoms than in patients (r = 0.98 versus 0.82, P < 0.001). Significantly more patients could be measured successfully using the XL probe than the M probe (98.4% versus 85.2%, respectively, P < 0.001) while the M probe produced a smaller interquartile range (21% versus 32%). Failure of the M probe to measure liver stiffness was not only observed in patients with a high body mass index and long skin-liver capsule distance but also in some nonobese patients (n = 10) due to quenching of the signal from subcutaneous fat tissue. In contrast with the phantoms, the XL probe consistently produced approximately 20% lower liver stiffness values in humans compared with the M probe. A long skin-liver capsule distance and a high degree of steatosis were responsible for this discordance. Adjustment of cutoff values for the XL probe (<5.5, 5.5&ndash;7, 7&ndash;10, and >10 kPa for F0, F1&ndash;2, F3, and F4 fibrosis, respectively) significantly improved agreement between the two probes from r = 0.655 to 0.679.Conclusion: Liver stiffness can be measured in significantly more obese and nonobese patients using the XL probe than the M probe. However, the XL probe is less accurate and adjusted cutoff values are required.Keywords: cirrhosis, liver fibrosis, liver stiffness, obesity, steatosis, transient elastography, M probe, XL prob

Free-Ranging Little Brown Myotis (Myotis lucifugus) Heal from Wing Damage Associated with White-Nose Syndrome

White-nose syndrome (WNS) is having an unprecedented impact on hibernating bat populations in the eastern United States. While most studies have focused on widespread mortality observed at winter hibernacula, few have examined the consequences of wing damage that has been observed among those bats that survive hibernation. Given that WNS-related wing damage may lead to life-threatening changes in wing function, we tested the hypothesis that reduced abundance of free-ranging little brown myotis (Myotis lucifugus) with severe wing damage as the summer progresses is due to healing of wing tissue. Photographs of captured and recaptured adult females were examined for wing damage and healing rates were calculated for each category of wing damage index (WDI = 0–3). We found that free-ranging bats with severe wing damage were able to heal to a lower WDI score within 2 weeks. Bats with the most severe wing damage had faster healing rates than did individuals with less damage. We also found a significant relationship between body condition and WDI for adult females captured in the early weeks of the active season. Our results support the hypothesis that some bats can heal from severe wing damage during the active season, and thus may not experience increased mortality associated with reduced functions of wings. We urge researchers and wildlife managers to use caution when interpreting data on WDI to assess the impact of WNS on bat populations, especially during the later months of the active season