医学データにおける統計的変換モデルの研究

科学研究費助成事業 研究成果報告書：研究活動スタート支援2016-2017課題番号 : 16H0746

SignalDetDDI: An SAS macro for detecting adverse drug-drug interactions in spontaneous reporting systems

Statistical methods for detecting adverse drug reactions (ADRs) resulting from drug-drug interactions (DDIs) have been used in recent years to analyze the datasets in spontaneous reporting systems. We provide the SignalDetDDI macro in SAS to calculate the criteria for detecting ADRs resulting from the concomitant use of two drugs. We outline two criteria for detecting DDIs with the combination of two drugs and illustrate the implementation of the macro by way of an example. To implement the macro, a user specifies the target ADR and the two drugs to be evaluated. The SignalDetDDI macro outputs a table showing the number of reports on ADRs, the values of the two criteria for detecting ADRs, and the presence of DDIs. This macro enables users to easily and automatically assess the clinical DDIs that result from ADRs

An Efficient Procedure for Calculating Sample Size Through Statistical Simulations

While planning clinical trials, when simple formulas are unavailable to calculate sample size, statistical simulations are used instead. However, one has to spend much computation time obtaining adequately precise and accurate simulated sample size estimates, especially when there are many scenarios for the planning and/or the specified statistical method is complicated. In this article, we summarize the theoretical aspect of statistical simulation-based sample size calculation. Then, we propose a new simulation procedure for sample size calculation by fitting the probit model to simulation result data. From the theoretical and simulation-based evaluations, it is suggested that the proposed simulation procedure provide more efficient and accurate sample size estimates than ordinary algorithm-based simulation procedure especially when estimated sample sizes are moderate to large, therefore it would help to dramatically reduce the computational time required to conduct clinical trial simulations

Correlation of motor-auditory cross-modal and auditory unimodal N1 and mismatch responses of schizophrenic patients and normal subjects: an MEG study

IntroductionIt has been suggested that the positive symptoms of schizophrenic patients (hallucinations, delusions, and passivity experience) are caused by dysfunction of their internal and external sensory prediction errors. This is often discussed as related to dysfunction of the forward model that executes self-monitoring. Several reports have suggested that dysfunction of the forward model in schizophrenia causes misattributions of self-generated thoughts and actions to external sources. There is some evidence that the forward model can be measured using the electroencephalography (EEG) and magnetoencephalography (MEG) components such as N1 (m) and mismatch negativity (MMN) (m). The objective in this MEG study is to investigate differences in the N1m and MMNm-like activity generated in motor-auditory cross-modal tasks in normal control (NC) subjects and schizophrenic (SC) patients, and compared that activity with N1m and MMNm in the auditory unimodal task.MethodsThe N1m and MMNm/MMNm-like activity were recorded in 15 SC patients and 12 matched NC subjects. The N1m-attenuation effects and peak amplitude of MMNm/MMNm-like activity of the NC and SC groups were compared. Additionally, correlations between MEG measures (N1m suppression rate, MMNm, and MMNm-like activity) and clinical variables (Positive and Negative Syndrome Scale (PANSS) scores and antipsychotic drug (APD) dosages) in SC patients were investigated.ResultsIt was found that (i) there was no significant difference in N1m-attenuation for the NC and SC groups, and that (ii) MMNm in the unimodal task in the SC group was significantly smaller than that in the NC group. Further, the MMNm-like activity in the cross-modal task was smaller than that of the MMNm in the unimodal task in the NC group, but there was no significant difference in the SC group. The PANSS positive symptoms and general psychopathology score were moderately negatively correlated with the amplitudes of the MMNm-like activity, and the APD dosage was moderately negatively correlated with the N1m suppression rate. However, none of these correlations reached statistical significance.DiscussionThe findings suggest that schizophrenic patients perform altered predictive processes differently from healthy subjects in latencies reflecting MMNm, depending on whether they are under forward model generation or not. This may support the hypothesis that schizophrenic patients tend to misattribute their inner experience to external agents, thus leading to the characteristic schizophrenia symptoms

Safety and Feasibility of Transcranial Direct Current Stimulation for Cognitive Rehabilitation in Patients With Mild or Major Neurocognitive Disorders: A Randomized Sham-Controlled Pilot Study

Introduction: Transcranial direct current stimulation (tDCS) is a potentially novel strategy for cognitive enhancement in patients with mild or major neurocognitive disorders. This study aims to assess the safety and efficacy of tDCS during cognitive training on cognitive functioning in patients with mild or major neurocognitive disorders.Methods: This study was primarily a single arm for safety, secondary a two-arm, parallel, randomized, and sham-controlled trial for potential efficacy. Patients with mild or major neurocognitive disorders were recruited. The participants and raters were blinded to the group assignment. The participants in the active arm received tDCS (anodal; F3, cathodal, Fp2, 2A, 20 min) twice daily for five consecutive days, whereas those in the sham arm received the same amount of sham-tDCS. Calculation and reading tasks were conducted in both arms as a form of cognitive intervention for 20 min during tDCS. The primary outcome was the attrition rate during the trial in the active arm, which is expected to be less than 10%. The secondary outcomes were the between-group differences of adjusted means for several cognitive scales from baseline to post-intervention and follow-up.Results: Twenty patients [nine women (45%)], with a mean (standard deviation) age of 76.1 years participated; nine patients (45%) with minor neurocognitive disorders and 11 (55%) with major neurocognitive disorders were randomized, and 19 of them completed the trial. The attrition rate in the active arm was 0%, with no serious adverse events. Further, in the Intention-to-Treat analysis, patients in the active arm showed no statistically significant improvement compared with those who received the sham in the mean change scores of the mini-mental state examination [0.41; 95% CI (−1.85; 2.67) at day five, 1.08; 95% CI (−1.31; 3.46) at follow-up] and Alzheimer’s disease assessment scale – cognition subscale [1.61; 95% CI (−4.2; 0.98) at day 5, 0.36; 95%CI (−3.19; 2.47) at follow-up].Conclusion: These findings suggest that tDCS is safe and tolerable but causes no statistically significant cognitive effects in patients with mild or major neurocognitive disorders. Additional large-scale, well-designed clinical trials are warranted to evaluate the cognitive effects of tDCS as an augmentation to cognitive training.Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT03050385

The association of single and combined factors of sedentary behavior and physical activity with subjective cognitive complaints among community-dwelling older adults: Cross-sectional study

Subjective cognitive complaints (SCC) might be a meaningful indicator of dementia onset or mild cognitive impairment, and identifying the related factors of SCC could contribute to preventing these diseases. However, the relationship between SCC and lifestyle factors remains largely unproven. The purpose of this study was to examine the association of type of sedentary behavior, physical activity, or their combination with SCC among community-dwelling older adults. In 2016, 6677 community-living elderly were recruited to participate in a survey investigating cognition, physical activity, and sedentary behavior. In total, 5328 participants responded to the questionnaire (79.8% valid response rate). SCC was assessed using the National Functional Survey Questionnaire (Kihon checklist). The relationships between SCC and physical activity, sedentary behavior (reading books or newspapers, and television viewing), or combined physical activity and sedentary behavior were examined via multiple logistic regression analysis. The analysis revealed that moderate-to-vigorous physical activity (≥150 min/week) was significantly related with a lower risk of SCC (odds ratio [OR] = 0.85; 95% confidence interval [CI] = 0.74–0.97), and that reading behavior showed a dose-response relationship with SCC (OR for 10–20 min/day = 0.63; 95% CI = 0.53–0.75; OR for 20–30 min/day = 0.59; 95% CI = 0.49–0.71; OR for ≥30 min/day = 0.47; 95% CI = 0.39–0.57). In addition, among those reporting high physical activity and ≥30 min/day for reading time, the OR for SCC was 0.40 (95% CI = 0.32–0.50) compared with the combined group reporting lower physical activity and non-readers. The present study shows that increased physical activity and reading time may be related to a reduced risk for SCC among community-dwelling older adults

Analysis of risk factors for mild cognitive impairment based on word list memory test results and questionnaire responses in healthy Japanese individuals registered in an online database

Although the development of effective therapeutic drugs and radical treatment options for dementia and Alzheimer’s disease (AD) remains urgent, progress in recent clinical trials of AD drugs has been less than adequate. In order to advance the progress of clinical trials, it is necessary to establish more efficient methods of recruitment. In Japan, there are registration systems stratified by mild cognitive impairment and preclinical and clinical stages of early and advanced stage dementia, but there is no registration system for healthy individuals yet. Therefore, in the present study, we developed a large-scale, internet-based health registry to investigate factors associated with cognitive function among registered participants. A total of 1038 participants completed the initial questionnaire and word list memory test. Among these participants, 353 individuals completed a second questionnaire and memory test. Stepwise multiple regression analysis was performed using IBM SPSS version 23.0 for Windows at a statistical significance level of p<0.05. We found that mood, motivation, and a decreased ability to perform activities of daily living were significantly associated with cognitive function. The results of the present study suggest that maintaining social involvement is important to prevent decreases in physical activity, daily function, mood, and motivation

Augmentation of Positive Valence System–Focused Cognitive Behavioral Therapy by Inaudible High-Frequency Sounds for Anhedonia : A Trial Protocol for a Pilot Study

Importance Recent conceptualizations in Research Domain Criteria have indicated that anhedonia, 1 of 2 core symptoms of depression, which can be treatment resistant, is associated with deficits in the positive valence system, and inaudible high-frequency sound therapy has been shown to enhance reward-related brain circuitry. Hence, cognitive behavioral therapy focusing on the positive valence system enhanced with sound therapy could have a synergistic effect on anhedonia.Objective To test the augmentation effect of inaudible high-frequency sounds on the efficacy of positive valence system–focused cognitive behavioral therapy to treat anhedonia.Design, Setting, and Participants In this individual-level allocation, exploratory, single-center randomized superiority pilot trial, patients, therapists, and evaluators will be masked to intervention or placebo assignment. The trial will take place at a national psychiatric referral hospital in Tokyo, Japan, among 44 adult patients with clinically significant anhedonia and moderate to severe depression. Outcomes will be analyzed following the intent-to-treat principle using a repeated-measures mixed model.Intervention The intervention group will participate in 8 weekly sessions of positive valence system–focused cognitive behavioral therapy with in-session exposure to an inaudible high-frequency sound; the comparison group will undergo cognitive behavioral therapy with in-session exposure to a placebo sound.Main Outcomes and Measures The primary outcome is anhedonia assessed using the self-reported Snaith-Hamilton Pleasure Scale. The secondary outcome is anhedonia assessed using the clinician-administered version of the Snaith-Hamilton Pleasure Scale.Discussion Recruitment for this study began in May 2018, and the projected date of final allocation is January 2020. A total of 21 eligible patients were registered for participation as of May 30, 2019. To date, treatments for depression do not guarantee clinically successful outcomes. This pilot trial will provide preliminary evidence of the augmentation effect of high-frequency inaudible sounds on cognitive behavioral therapy for anhedonia. Overall, exposure to an inaudible high-frequency sounds does not require attentional or cognitive effort from either patients or therapists; therefore, results from a future confirmative trial could indicate that cognitive behavioral therapy can be augmented in an effortless manner

Cognitive behavioral therapy with interoceptive exposure and complementary video materials for irritable bowel syndrome (IBS): protocol for a multicenter randomized controlled trial in Japan

BackgroundThere is growing evidence of the treatment efficacy of cognitive behavioral therapy (CBT) for irritable bowel syndrome (IBS). CBT is recommended by several practice guidelines for patients with IBS if lifestyle advice or pharmacotherapy has been ineffective. Manual-based CBT using interoceptive exposure (IE), which focuses on the anxiety response to abdominal symptoms, has been reported to be more effective than other types of CBT. One flaw of CBT use in general practice is that it is time and effort consuming for therapists. Therefore, we developed a set of complementary video materials that include psycho-education and homework instructions for CBT patients, reducing time spent in face-to-face sessions while maintaining treatment effects. The purpose of this study is to examine the effects of CBT-IE with complementary video materials (CBT-IE-w/vid) in a multicenter randomized controlled trial (RCT).MethodsThis study will be a multicenter, parallel-design RCT. Participants diagnosed with IBS according to the Rome IV diagnostic criteria will be randomized to either the treatment as usual (TAU) group or the CBT-IE-w/vid + TAU group. CBT-IE-w/vid consists of 10 sessions (approximately 30 min face-to-face therapy + viewing a video prior to each session). Patients in the CBT-IE-w/vid group will be instructed to pre- view 3- to 13-min videos at home prior to each face-to-face therapy visit at a hospital. The primary outcome is the severity of IBS symptoms. All participants will be assessed at baseline, mid-treatment, post-treatment, and follow-up (3 months after post assessment). The sample will include 60 participants in each group.DiscussionTo our knowledge, this study will be the first RCT of manual-based CBT for IBS in Japan. By using psycho-educational video materials, the time and cost of therapy will be reduced. Manual based CBTs for IBS have not been widely adopted in Japan to date. If our CBT-IE-w/vid program is confirmed to be more effective than TAU, it will facilitate dissemination of cost-effective manual-based CBT in clinical settings