Test Procedures for Disease Prevalence with Partially Validated Data

Investigating the prevalence of a disease is an important topic in medical studies. Such investigations are usually based on the classification results of a group of subjects according to whether they have the disease. To classify subjects, screening tests that are inexpensive and nonintrusive to the test subjects are frequently used to produce results in a timely manner. However, such screening tests may suffer from high levels of misclassification. Although it is often possible to design a gold-standard test or device that is not subject to misclassification, such devices are usually costly and time-consuming, and in some cases intrusive to the test subjects. As a compromise between these two approaches, it is possible to use data that are obtained by the method of double-sampling. In this article, we derive and investigate four test statistics for testing a hypothesis on disease prevalence with double-sampling data. The test statistics are implemented through both the asymptotic method suitable for large samples and approximate unconditional method suitable for small samples. Our simulation results show that the approximate unconditional method usually produces a more satisfactory empirical type I error rate and power than its asymptotic counterpart, especially for small to moderate sample sizes. The results also suggest that the score test and the Wald test based on an estimate of variance with parameters estimated under the null hypothesis outperform the others. An real example is used to illustrate the proposed methods.     

Erratum to: Inflammation in Patients with Schizophrenia: The Therapeutic Benefits of Risperidone Plus Add-On Dextromethorphan

Journal of Neuroimmune Pharmacology -     

The Effects of Bi-Anodal tDCS Over the Prefrontal Cortex Regions With Extracephalic Reference Placement on Insight Levels and Cardio-Respiratory and Autonomic Functions in Schizophrenia Patients and Exploratory Biomarker Analyses for Treatment Response

BackgroundWe previously showed the efficacy of bi-anodal transcranial direct current stimulation (tDCS) over the prefrontal cortex (PFC) regions with extracephalic reference placement in improving negative symptoms in schizophrenia. In this ancillary investigation, the effects of this intervention on insight levels, other clinical outcomes, and cardio-respiratory and autonomic functions were examined and the potential of biomarkers for treatment response was explored.MethodsSchizophrenia patients were randomly allocated to receive 10 sessions of bi-anodal tDCS over the PFC regions with extracephalic reference placement (2 mA, 20 minutes, twice daily for 5 weeks) or sham stimulation. We examined, in 60 patients at baseline, immediately after stimulation and at follow-up visits, the insight levels, other clinical outcomes, blood pressure, respiratory rate, heart rate, and heart rate variability.ResultsInsight levels as assessed by the abbreviated version of the Scale to Assess Unawareness in Mental Disorder in schizophrenia awareness of the disease, positive and negative symptoms dimensions, and beliefs about medication compliance as assessed by Medication Adherence Rating Scale were significantly enhanced by active stimulation relative to sham. No effects were observed on cognitive insight, other clinical outcomes, or cardio-respiratory and autonomic functions. Heart rate variability indices as biomarkers were not associated with the clinical response to the intervention.ConclusionsOur results provide evidence for bi-anodal tDCS over the PFC regions with extracephalic reference placement in heightening the levels of insight into the disease and symptoms, as well as beliefs about medication compliance in schizophrenia, without impacting other clinical outcomes and cardio-respiratory/autonomic functions.     

A Placebo-Controlled Trial of Dextromethorphan as an Adjunct in Opioid-Dependent Patients Undergoing Methadone Maintenance Treatment

Background:

Low-dose dextromethorphan (DM) might have anti-inflammatory and neurotrophic effects mechanistically remote from an NMDA receptor. In a randomized, double-blind, controlled 12 week study, we investigated whether add-on dextromethorphan reduced cytokine levels and benefitted opioid-dependent patients undergoing methadone maintenance therapy (MMT).

Methods:

Patients were randomly assigned to a group: DM60 (60mg/day dextromethorphan; n = 65), DM120 (120mg/day dextromethorphan; n = 65), or placebo (n = 66). Primary outcomes were the methadone dose required, plasma morphine level, and retention in treatment. Plasma tumor necrosis factor (TNF)-α, C-reactive protein, interleukin (IL)-6, IL-8, transforming growth factor–β1, and brain-derived neurotrophic factor (BDNF) levels were examined during weeks 0, 1, 4, 8, and 12. Multiple linear regressions with generalized estimating equation methods were used to examine the therapeutic effect.

Results:

After 12 weeks, the DM60 group had significantly longer treatment retention and lower plasma morphine levels than did the placebo group. Plasma TNF-α was significantly decreased in the DM60 group compared to the placebo group. However, changes in plasma cytokine levels, BDNF levels, and the methadone dose required in the three groups were not significantly different.

Conclusions:

We provide evidence—decreased concomitant heroin use—of low-dose add-on DM’s efficacy for treating opioid-dependent patients undergoing MMT.     

Generalized Anxiety Disorder,Comorbid Major Depression and Heart Rate Variability: A Case-Control Study in Taiwan

Objective

Decreased heart rate variability (HRV) has been reported in generalized anxiety disorder (GAD), but the results are mixed. Little is known about the impact of comorbid major depression (MD) on HRV in GAD patients. Both issues necessitate further investigation.

Methods

Twenty unmedicated, physically healthy GAD patients, 20 GAD patients with a secondary diagnosis of MD, 40 MD patients and 60 matched controls were recruited. We used the Hamilton Anxiety Rating Scale and the Hamilton Depression Rating Scale to assess anxiety and depression severity, respectively. Cardiac autonomic function was evaluated by measuring HRV parameters. Frequency-domain indices of HRV were obtained.

Results

Three patient groups had more anxiety and depression symptoms than control subjects, but heart rates (HRs) were significantly elevated only in GAD patients with comorbid depression. Relative to controls, GAD patients had reduced HRV while GAD patients with comorbid depression displayed the greatest reductions in HRV among three patients groups. Correlation analyses revealed anxiety/depression severity significantly associated with HRs, variance, LF-HRV and HF-HRV. However, separately analyzing among individual groups and adjusting for HRV-associated covariables rendered the correlations non-significant.

Conclusion

Our results suggest that reduction in HRV is a psychophysiological marker of GAD and individuals with comorbid GAD and MD may be distinguished based on psychophysiological correlates (for example, HF-HRV) from non-comorbid GAD patients. Taken into account that comorbid depression may confer increased risks for cardiovascular events in GAD patients, this subgroup of GAD patients may benefit better from cardiovascular risk reduction strategies.     

Tests of noninferiority via rate difference for three-arm clinical trials with placebo

In assessing a noninferiority trial, the investigator intends to show efficacy by demonstrating that a new experimental drug/treatment is not worse than a known active control/reference by a small predefined margin. If it is ethically justifiable, it may be advisable to include an additional placebo group for internal validation purpose. This constitutes the well-known three-arm clinical trial with placebo. In this paper, we study two asymptotic statistical methods for testing of noninferiority in three-arm clinical trials with placebo for binary outcomes based on rate difference. They are sample-based estimation method and restricted maximum likelihood estimation method, respectively. We investigate the performance of the proposed test procedures under different sample size allocation settings via a simulation study. Both methods perform satisfactorily under moderate to large sample settings. However, the restricted maximum likelihood estimation method usually possesses slightly smaller actual type I error rates, which are relatively close to the prespecified nominal level, while the sample-based method can be expressed in a simple closed-form format. Real examples from a pharmacological study of patients with functional dyspepsia and a placebo-controlled trial of subjects with acute migraine are used to demonstrate our methodologies.     

劳拉西泮与碳酸锂治疗躁狂症的比较

目的：评估劳拉西泮对躁狂症的疗效。方法：用劳拉西泮治疗男性躁狂症１９例（年龄２８±ｓ１０ａ，病程２．０±１．３ｍｏ），剂量６～１８ｍｇ／ｄ，疗程３ｗｋ，并与碳酸锂治疗男性躁狂症２０例（年龄２８±１１ａ，病程２．０±１．３ｍｏ）对照，剂量１．５～２．５ｇ／ｄ，疗程３ｗｋ。结果：劳拉西泮组，总有效率８９％，碳酸锂组，总有效率９５％（Ｐ＞０．０５），但劳拉西泮起效时间较碳酸锂为早，不良反应以嗜唾、头晕为主。结论：劳拉西泮可作为控制躁狂症急性发作的有效药物。