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For ordered categorical data from randomized clinical trials, the relative effect, the probability that observations in one group tend to be larger, has been considered appropriate for a measure of an effect size. Although the Wilcoxon–Mann–Whitney test is widely used to compare two groups, the null hypothesis is not just the relative effect of 50%, but the identical distribution between groups. The null hypothesis of the Brunner–Munzel test, another rank-based method used for arbitrary types of data, is just the relative effect of 50%. In this study, we compared actual type I error rates (or 1 – coverage probability) of the profile-likelihood-based confidence intervals for the relative effect and other rank-based methods in simulation studies at the relative effect of 50%. The profile-likelihood method, as with the Brunner– Munzel test, does not require any assumptions on distributions. Actual type I error rates of the profile-likelihood method and the Brunner–Munzel test were close to the nominal level in large or medium samples, even under unequal distributions. Those of the Wilcoxon–Mann–Whitney test largely differed from the nominal level under unequal distributions, especially under unequal sample sizes. In small samples, the actual type I error rates of Brunner–Munzel test were slightly larger than the nominal level and those of the profile-likelihood method were even larger. We provide a paradoxical numerical example: only the Wilcoxon–Mann–Whitney test was significant under equal sample sizes, but by changing only the allocation ratio, it was not significant but the profile-likelihood method and the Brunner–Munzel test were significant. This phenomenon might reflect the nature of the Wilcoxon–Mann–Whitney test in the simulation study, that is, the actual type I error rates become over and under the nominal level depending on the allocation ratio. [ABSTRACT FROM AUTHOR]

Objective To determine smoking trends in Japan in comparison with lung cancer mortality. Methods Age-specific smoking prevalence among cohorts born between 1897 and 1985 were determined for the period 1949- 2010. The percentages of the cohorts born between 1893 and 1979 who initiated smoking early (e.g. before the age of 20 years) were determined. The results were compared against lung cancer mortality rates in people aged 40-84 years belonging to cohorts born between 1868 and 1968. Findings In males, smoking prevalence was generally high, particularly among those born before the late 1950s, and early initiation was fairly uncommon. Early initiation was most common among recent birth cohorts of males, who showed relatively low prevalences of smoking. In females, the prevalence of smoking was generally low and early initiation was very uncommon, particularly among those born in the late 1930s and before the late 1940s, respectively. Recent cohorts of females showed relatively high prevalences of smoking and relatively high percentages of early initiation. In both sexes, lung cancer mortality was generally low but increased over the study period. Conclusion Lung cancer mortality in Japanese males was relatively low given the high prevalence of smoking, perhaps because early initiation was fairly uncommon. Over the last four decades, however, early initiation of smoking has become more common in both sexes. The adverse effect this is likely to have on lung cancer mortality rates has probably not been observed because of the long time lag. Objectif Determiner les tendances du tabagisme au Japon comparees a la mortalite par cancer du poumon. Methodes Les taux de prevalence du tabagisme en fonction de l'age, parmi les cohortes nees entre 1897 et 1985, ont ete determines pour la periode 1949-2010. Les pourcentages des cohortes nees entre 1893 et 1979, ayant commence a fumer de maniere precoce (par exemple avant l'age de 20 ans), ont ete determines. Les resultats ont ete compares aux taux de mortalite par cancer du poumon chez les personnes agees de 40 a 84 ans, appartenant aux cohortes nees entre 1868 et 1968. Resultats Chez les hommes, la prevalence du tabagisme etait generalement elevee, en particulier parmi les personnes nees avant les annees 1950, et l'initiation precoce etait assez peu frequente. L'initiation precoce etait plus frequente parmi les cohortes de naissances d'hommes, montrant des prevalences relativement faibles de tabagisme. Chez les femmes, la prevalence du tabagisme etait generalement faible, et rinitiation precoce tres peu frequente, en particulier chez les personnes nees dans les annees 1930 et avant les annees 1940, respectivement. Les cohortes recentes de retomes ont montre des prevalences relativement elevees de tabagisme et des pourcentages relativement eleves d'initiation precoce. Pour les deux sexes, la mortalite par cancer du poumon etait generalement faible, mais elle a augmente au cours de la periode etudiee. Conclusion La mortalite par cancer du poumon chez les hommes japonais etait relativement faible compte tenu de la forte prevalence du tabagisme, peut-etre parce que l'initiation precoce etait assez rare. Au cours des quatre dernieres decennies cependant, rinitiation precoce du tabagisme s'est davantage repandue chez les deux sexes. l'effet negatif que cela peut avoir sur les taux de mortalite par cancer du poumon n'a pas ete observe, probablement en raison du decalage. Objetivo Conocer las prevalencias del tabaquismo en Japon respecto a la mortalidad por cancer de pulmon. Metodos Se determinaron los indices de prevalencia dei tabaquismo por edad entre cohortes nacidas entre 1897 y 1985 para el periodo 1949-2010. Se establecieron los porcentajes de las cohortes nacidas entre 1893 y 1979 que iniciaron el consumo de tabaco a edad temprana (por ejemplo, antes de los 20 anos de edad). Se contrastaron los resultados con los indices de mortalidad por cancer de pulmon en personas entre los 40 y 84 anos de edad que pertenecian a cohortes nacidas entre 1868 y 1968. Resultados En varones, el indice de prevalencia del tabaquismo resulto ser generalmente alto, particularmente entre aquellos nacidos antes del final de la decada de 1950; asimismo, la iniciacion temprana fue inusual. Esta resulto ser mas comun entre las cohortes de nacimiento varones recientes, quienes mostraron una prevalencia del tabaquismo relativamente baja. En mujeres, el indice de prevalencia del tabaquismo resulto ser generalmente bajo y la iniciacion temprana fue muy poco comun, en particular entre aquellas nacidas a finales de la decada de 1930 y antes de finales de la decada de 1940, respectivamente. Las cohortes de mujeres recientes mostraron una prevalencia del tabaquismo relativamente alta, asi como porcentajes de iniciacion temprana relativamente altos. En ambos sexos, la mortalidad por cancer de pulmon resulto ser generalmente baja, aunque incremento a lo largo del periodo de estudio. Conclusion La mortalidad por cancer de pulmon en varones japoneses fue relativamente baja, si se compara con la alta prevalencia del tabaquismo. Quiza esto se deba a que la iniciacion temprana fue poco comun. No obstante, en las ultimas cuatro decadas la iniciacion temprana ai tabaquismo es mas comun en ambos sexos. Posiblemente, no se ha observado el efecto adverso que esto pueda tener sobre los indices de mortalidad por cancer de pulmon debido al gran lapso temporal., Introduction Although smoking is known to cause cancer, cardiovascular and respiratory diseases and other health problems, (1) almost one billion men and 250 million women in the world smoke. (2) [...]

For continuous variables of randomized controlled trials, recently, longitudinal analysis of pre‐ and posttreatment measurements as bivariate responses is one of analytical methods to compare two treatment groups. Under random allocation, means and variances of pretreatment measurements are expected to be equal between groups, but covariances and posttreatment variances are not. Under random allocation with unequal covariances and posttreatment variances, we compared asymptotic variances of the treatment effect estimators in three longitudinal models. The data‐generating model has equal baseline means and variances, and unequal covariances and posttreatment variances. The model with equal baseline means and unequal variance–covariance matrices has a redundant parameter. In large sample sizes, these two models keep a nominal type I error rate and have high efficiency. The model with equal baseline means and equal variance–covariance matrices wrongly assumes equal covariances and posttreatment variances. Only under equal sample sizes, this model keeps a nominal type I error rate. This model has the same high efficiency with the data‐generating model under equal sample sizes. In conclusion, longitudinal analysis with equal baseline means performed well in large sample sizes. We also compared asymptotic properties of longitudinal models with those of the analysis of covariance (ANCOVA) and t‐test. [ABSTRACT FROM AUTHOR]

The assessment of the dose-response relationship is important but not straightforward when the therapeutic agent is administered repeatedly with dose-modification in each patient and a continuous response is measured repeatedly. We recently proposed an autoregressive linear mixed effects model for such data in which the current response is regressed on the previous response, fixed effects, and random effects. The model represents profiles approaching each patient's asymptote, takes into account the past dose history, and provides a dose-response relationship of the asymptote as a summary measure. In an autoregressive model, intermittent missing data mean the missing values in previous responses as covariates. We previously provided the marginal (unconditional on the previous response) form of the proposed model to deal with intermittent missing data. Irregular timings of dose-modification or measurement can also be treated as equally spaced data with intermittent missing values by selecting an adequately small unit of time. The likelihood is, however, expressed by matrices whose sizes depend on the number of observations for a patient, and the computational burden is large. In this study, we propose a state space form of the autoregressive linear mixed effects model to calculate the marginal likelihood without using large matrices. The regression coefficients of the fixed effects can be concentrated out of the likelihood in this model by the same way of a linear mixed effects model. As an illustration of the approach, we analyzed immunologic data from a clinical trial for multiple sclerosis patients and estimated the dose-response curves for each patient and the population mean. Copyright © 2011 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

In clinical trials, sometimes only a single drug concentration can be measured from a patient, because of the burden on the patient. From a single concentration, we cannot generally obtain point estimates of each pharmacokinetic parameter in a patient. In this article, we propose a method to estimate the clearance using a one-compartment model of a single-bolus intravenous injection from a single concentration at a sampling point between 1.5 and 2.5 half-lives. This method requires an assumed value for the volume of distribution but is robust to misspecification. This approach is illustrated by simulated concentration data and cadralazine concentration data. [ABSTRACT FROM PUBLISHER]

Objectives: Limited information is available on the use of biologics in patients with systemic sclerosis (SSc) or SSc-associated interstitial lung disease (SSc-ILD) in Japan. The types of biologics, treatment duration, treatment prior to biologics, concomitant treatment, and characteristics of patients receiving biologics were investigated., Methods: We used a Japanese hospital claims database provided by Medical Data Vision Co. (2008-2021)., Results: In the database, 1186 of 34,207 SSc patients (3.5%) and 620 of 12,303 SSc-ILD patients (5.0%) received anti-interleukin-6 (anti-IL-6) drugs, anti-tumour necrosis factor (anti-TNF) drugs, abatacept, or rituximab. The most common were anti-IL-6 drugs [used in 35.5% of SSc patients and 38.5% of SSc-ILD patients (tocilizumab, 34.5% and 36.6%)], followed by anti-TNF drugs [31.3% and 26.5% (etanercept, 10.5% and 9.0%; others, <8%)], abatacept (17.5% and 20.6%), and rituximab (15.7% and 14.4%). Among SSc and SSc-ILD patients treated with anti-IL-6 drugs, anti-TNF drugs, or abatacept, the most common immunosuppressive drugs prior to initiation of biologics were methotrexate and tacrolimus. Approximately half of patients receiving anti-IL-6 drugs, anti-TNF drugs, or abatacept continued treatment beyond 1 year., Conclusions: Our study indicates that off-label biologics have been used in a certain number of SSc or SSc-ILD patients in Japan, with tocilizumab the most common., (© Japan College of Rheumatology 2022. Published by Oxford University Press.)

Objectives: Limited information is available on patients with systemic sclerosis (SSc) or SSc-associated interstitial lung disease (SSc-ILD) receiving mycophenolate mofetil (MMF) in Japan. The dose, treatment duration, and patient characteristics of SSc and SSc-ILD patients receiving MMF were investigated., Methods: We used data from a Japanese hospital claims database (2008-2020)., Results: Data on 486 SSc patients ≥18 years old receiving MMF were captured; 314 had SSc complicated with ILD. The most common initial daily doses were 1000 mg (SSc, 39.5%; SSc-ILD, 38.1%) and 500 mg (SSc, 36.6%; SSc-ILD, 34.6%). The most common maximum daily doses were 1000 mg (SSc, 33.3%; SSc-ILD, 34.9%), 1500 mg (SSc, 24.4%; SSc-ILD, 23.1%), and 2000 mg (SSc, 23.8%; SSc-ILD, 24.4%). Doses ranged from 250 to 3000 mg/day and were similar for SSc and SSc-ILD patients. Over 27% of patients received treatment for >1 year. There was a gradual decrease in steroid doses during MMF treatment., Conclusions: Our study suggests that the off-label use of MMF for SSc and SSc-ILD has been increasing annually since 2015 in Japan. The doses used in patients with SSc and SSc-ILD were similar to the approved doses of MMF for lupus nephritis in Japan., (© Japan College of Rheumatology 2021. Published by Oxford University Press.)