Statistical Methods for Targeted Clinical Trials under Enrichment Design

Background/PurposeAfter completion of the Human Genome Project, disease targets at the molecular level can be identified. Treatment for these specific targets can be developed with the individualized treatment of patients becoming a reality. However, the accuracy of diagnostic devices for molecular targets is not perfect and statistical inference for treatment effects of the targeted therapy is biased. We developed statistical methods for an unbiased inference for the targeted therapy in patients who truly have the molecular targets.MethodsUnder the enrichment design, for binary data, we propose using the expectation maximization (EM) algorithm with the bootstrap method, to incorporate the inaccuracy of the diagnostic device for detection of the molecular targets for inference of the treatment effects. A simulation study was conducted to empirically investigate the performance of the proposed estimation and testing procedures. A numerical example illustrates the application of the proposed method.ResultsSimulation results demonstrated that the proposed estimation method was unbiased, with adequate precision, and the confidence interval provided satisfactory coverage probability. The proposed testing procedure adequately controlled the size with sufficient power. The numerical example showed that a statistically significant treatment effect could be obtained when the inaccuracy of the diagnostic device was taken into account.ConclusionOur proposed estimation and testing procedures are adequate statistical methods for the inference of the treatment effect for patients who truly have the molecular targets

The Efficacy and Safety of a Fixed Combination of Chinese Herbal Medicine in Chronic Urticaria: A Randomized, Double-Blind, Placebo-Controlled Pilot Study

Background: Chronic urticaria is a bothersome skin disease, and Chinese herbal medicine (CHM) is commonly used as adjuvant therapy. This study aimed to evaluate the effectiveness and safety of the mixture of two CHM formula, Xiao-Feng-San (XFS) and Qing-Shang-Fang-Feng-Tang (QSFFT), in treating urticaria through a randomized, double-blind, placebo-controlled clinical trial.Methods: 78 participants entered the screening phase between November 2012 and August 2015. Participants were randomly and equally allocated in either CHM group (2 gm XFS and 2 gm QSFFT four times a day and 5 mg levocetirizine once daily for 28 days followed by 5 mg levocetirizine once daily alone for 28 days) or control group (placebo and 5 mg levocetirizine daily followed by 5 mg levocetirizine once daily for 28 days alone). Symptom improvement was set as the primary outcome, and the influence on sleep quality and changes in serum markers were used as secondary outcomes. Per protocol design was applied to the final analysis.Results: A total of 56 participants entered the final analysis stage. Participants in the CHM group had more prominent symptom relief on day 56 (the weekly urticaria activity score, UAS7, as 9.9 ± 9.2 vs. 15.6 ± 10.8, p = 0.038). In the CHM group, participants' symptom severity reduced progressively (trend analysis, p < 0.001) while the decreasing trend was less favored in the control group (trend analysis, p = 0.056). The life quality improved gradually in both groups, while the differences between CHM and control groups were statistically insignificant. For urticaria-related cytokines, interferon-γ seemed to decrease positively in the CHM group (about 30.8% reduction from baseline, trend analysis p = 0.013). For safety issue, the CHM prescription was well-tolerated with no noticeable long-term side effects when compared to the control group. At 6-month follow-up of symptom changes after the end of the trial, the CHM group participants reported positive results in no recurrence or ≥50% improvement (36.3% in CHM group vs. 20% in Control group, p = 0.103).Conclusions: The combination of XFS and QSFFT tended to be feasible and tolerable adjuvant therapy for urticaria in addition to standard therapy. However, larger study population with longer follow-up duration may be still needed.Trial registration: NCT01715740 (ClinicalTrials.gov)

Clinical Study Analgesic Effects of Intra-Articular Bupivacaine/Intravenous Parecoxib Combination Therapy versus Intravenous Parecoxib Monotherapy in Patients Receiving Total Knee Arthroplasty: A Randomized, Double-Blind Trial

Objectives. The purpose of this double-blind, randomized study was to investigate whether the addition of intra-articular bupivacaine to intravenous parecoxib could improve pain relief in patients undergoing total knee arthroplasty. Methods. A total of 36 patients undergoing total knee arthroplasty were enrolled into our study. These patients were randomly allocated either to a placebo-controlled group or study group. Postoperative pain scores and analgesic consumption were evaluated. Results. Numeric rating scale (NRS) data of bupivacaine group in postoperative room were significantly lower than that of control group (control group versus bupivacaine group, 7.9 (6.7-9.1) (mean and 95% confidence interval) versus 4.5 (3.2-5.8) (mean and 95% confidence interval), = 0.001). NRS data of bupivacaine group in ward were also significantly lower than that of control group. A significantly lower dose of meperidine was used in the study group postoperatively during the first 24 hours (control group versus bupivacaine group, 3.08 ± 0.80 mg/Kg versus 2.34 ± 0.42 mg/Kg, = 0.001). Conclusion. Intra-articular bupivacaine in combination with intravenous parecoxib may improve pain relief and reduce the demand for rescue analgesics in patients undergoing total knee arthroplasty. The trial is registered with Australian New Zealand Clinical Trials Registry (ACTRN12615000463572)

Recapitulation of Fibromatosis Nodule by Multipotential Stem Cells in Immunodeficient Mice

Musculoskeletal fibromatosis remains a disease of unknown etiology. Surgical excision is the standard of care, but the recurrence rate remains high. Superficial fibromatosis typically presents as subcutaneous nodules caused by rapid myofibroblast proliferation followed by slow involution to dense acellular fibrosis. In this study, we demonstrate that fibromatosis stem cells (FSCs) can be isolated from palmar nodules but not from cord or normal palm tissues. We found that FSCs express surface markers such as CD29, CD44, CD73, CD90, CD105, and CD166 but do not express CD34, CD45, or CD133. We also found that FSCs are capable of expanding up to 20 passages, that these cells include myofibroblasts, osteoblasts, adipocytes, chondrocytes, hepatocytes, and neural cells, and that these cells possess multipotentiality to develop into the three germ layer cells. When implanted beneath the dorsal skin of nude mice, FSCs recapitulated human fibromatosis nodules. Two weeks after implantation, the cells expressed immunodiagnostic markers for myofibroblasts such as α-smooth muscle actin and type III collagen. Two months after implantation, there were fewer myofibroblasts and type I collagen became evident. Treatment with the antifibrogenic compound Trichostatin A (TSA) inhibited the proliferation and differentiation of FSCs in vitro. Treatment with TSA before or after implantation blocked formation of fibromatosis nodules. These results suggest that FSCs are the cellular origin of fibromatosis and that these cells may provide a promising model for developing new therapeutic interventions

Efficacious Intermittent Dosing of a Novel JAK2 Inhibitor in Mouse Models of Polycythemia Vera

A high percentage of patients with the myeloproliferative disorder polycythemia vera (PV) harbor a Val617→Phe activating mutation in the Janus kinase 2 (JAK2) gene, and both cell culture and mouse models have established a functional role for this mutation in the development of this disease. We describe the properties of MRLB-11055, a highly potent inhibitor of both the WT and V617F forms of JAK2, that has therapeutic efficacy in erythropoietin (EPO)-driven and JAK2V617F-driven mouse models of PV. In cultured cells, MRLB-11055 blocked proliferation and induced apoptosis in a manner consistent with JAK2 pathway inhibition. MRLB-11055 effectively prevented EPO-induced STAT5 activation in the peripheral blood of acutely dosed mice, and could prevent EPO-induced splenomegaly and erythrocytosis in chronically dosed mice. In a bone marrow reconstituted JAK2V617F-luciferase murine PV model, MRLB-11055 rapidly reduced the burden of JAK2V617F-expressing cells from both the spleen and the bone marrow. Using real-time in vivo imaging, we examined the kinetics of disease regression and resurgence, enabling the development of an intermittent dosing schedule that achieved significant reductions in both erythroid and myeloid populations with minimal impact on lymphoid cells. Our studies provide a rationale for the use of non-continuous treatment to provide optimal therapy for PV patients

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Statistical Inference on Treatment Effects for Targeted Clinical Trials under Enrichment Design

於人類基因體計畫完成後，疾病的分子標的可被鑑別，因此可以發展出分子標的形式的治療方法。在實務上，標的臨床試驗通常是用來評估個別化臨床處置的可能性及可行性。但是鑑定分子標的之診斷試劑通常並非完全準確，所以有些納入標的臨床試驗的陽性診斷病人實際上可能並沒有此分子標的，因此對於真正擁有分子標的之病人族群而言，標的臨床試驗下之標的療法的療效估計值會有偏差。 因此對於真正擁有分子標的之病人，我們則提出標的療法之無偏推論的統計方法。在強化設計的臨床試驗下，考慮鑑定分子標的之診斷試劑的準確度，我們提出利用EM演算法配合拔靴技術與貝氏方法來做處理效應之推論。運用模擬研究以驗證所得之估計值與檢定程序，並提出實例數據以說明方法的應用。對於推論真正擁有分子標的之病人族群的療效，我們所提出的之估計值及檢定程序為適當的統計方法。After completion of the Human Genome Project (HGP), the disease targets at molecular levels can be identified. As a result, treatment modality for molecular targets can be developed. In practice, targeted clinical trials are usually conducted for evaluation of the possibility and feasibility of the individualized treatment of patients. However, the accuracy of diagnostic devices for identification of such molecular targets is usually not perfect. Therefore, some of the patients enrolled in targeted clinical trials with a positive result for molecular target might not have the specific molecular targets and hence the treatment effects of the targeted therapy estimated from targeted clinical trials could be biased for the patient population truly with the molecular targets. We develop statistical methods for an unbiased inference for the targeted therapy in the patients truly with the molecular targets. Under the enrichment design, we propose using the EM algorithm in conjunction with the bootstrap technique and the Bayesian method to incorporate the inaccuracy of the diagnostic device for detection of the molecular targets on the inference of the treatment effects. The simulation studies were conducted to empirically investigate the performance of the proposed estimations and testing procedures. Numerical example illustrates the application of the proposed method. Our proposed estimations and testing procedures are adequate statistical methods for the inference of the treatment effects for the patients truly with molecular targets.CHAPERT 1 INTRODUCTION 1.1 ACCURACY OF DIAGNOSTIC DEVICES 3.2 STATISTICAL DESIGNS 8.3 SUMMARY 13HAPERT 2 LITERATURE REVIEW 15.1 STATISTICAL METHODS UNDER ENRICHMENT DESIGN 16.2 EM ALGORITHM 17.3 CONVERGENCE OF EM ALGORITHM 18.4 ESTIMATOR OF THE STANDARD ERROR 19.5 MARKOV CHAIN MONTE CARLO (MCMC) 20.6 CONJUGATE PRIORS 22.7 GIBBS SAMPLER 25HAPERT 3 STATISTICAL INFERENCE TO CONTINUOUS ENDPOINTS 27.1 CURRENT METHODS 27.2 THE PROPOSED PROCEDURE 30.3 SAMPLE SIZE CALCULATION 37HAPERT 4 STATISTICAL INFERENCE TO BINARY ENDPOINTS 39.1 CURRENT METHODS 39.2 THE PROPOSED PROCEDURE 42HAPERT 5 SIMULATION STUDIES 47.1 CONTINUOUS ENDPOINTS 47.1.1 Simulation Procedure 47.1.2 Simulation Results 49.2 BINARY ENDPOINTS 53.2.1 Simulation Procedure 53.2.2 Simulation Results 54HAPERT 6 NUMERIC EXAMPLES 77.1 CONTINUOUS ENDPOINTS 77.2 BINARY ENDPOINTS 79HAPERT 7 DISCUSSION 85EFERENCES 99PPENDIX A 10

The Clarus Video System (Trachway) and direct laryngoscope for endotracheal intubation with cricoid pressure in simulated rapid sequence induction intubation: a prospective randomized controlled trial

Abstract Background During an emergency endotracheal intubation, rapid sequence induction intubation (RSII) with cricoid pressure (CP) is frequently implemented to prevent aspiration pneumonia. We evaluated the CVS in endotracheal intubation in RSII with CP, in comparison with a direct laryngoscope (DL). Methods One hundred fifty patients were randomly assigned to one of three groups: the CVS as a video stylet (CVS-V) group, the CVS as a lightwand (CVS-L) group and DL group. Primary outcomes were to assess the power of the CVS, compared with DL, regarding the first attempt success rate and intubation time in simulated RSII with CP. Secondary outcomes were to examine hemodynamic stress response and the incidence of complications. Results The first attempt success rates within 30 s and within 60 s were higher in CVS-V and DL group than those in CVS-L group (p = 0.006 and 0.037, respectively). The intergroup difference for intubation success rate within 30 s was nonsignificant and almost all the patients were successfully intubated within 60 s (98% for CVS-L and DL group, 96% for CVS-L group). Kaplan-Meier estimator demonstrated the median intubation time was 10.6 s [95% CI, 7.5 to 13.7] in CVS-V group, 14.6 s [95% CI, 11.1 to 18.0] in CVS-L group and 16.5 s [95% CI, 15.7 to 17.3] in DL group (p = 0.023 by the log-rank test). However, the difference was nonsignificant after Sidak’s adjustment. The intergroup differences for hemodynamic stress response, sore throat and mucosa injury incidence were also nonsignificant. Conclusions The CVS-D and DL provide a higher first attempt intubation success rate within 30 and 60 s in intubation with CP; the intubation time for the CVS-V was nonsignificantly shorter than that for the other two intubation methods. Almost all the patients can be successfully intubated with any of the three intubation methods within 60 s. Trial registration ClinicalTrials.gov identifier: NCT03841890, registered on February 15, 2019 (retrospectively registered)

Clinical outcomes for primary molars treated by different types of pulpotomy: A retrospective cohort study

Pulpotomy is the amputation of coronally infected pulp tissue to maintain the vitality and function of the radicular pulp. This study was designed to assess the clinical and radiographic success rates of primary molars treated by pulpotomy using diode laser, sodium hypochlorite, or no medication after a follow-up period of 24 months. Methods: A retrospective study was conducted by evaluating the success rates of primary molars treated by pulpotomy with diode laser, sodium hypochlorite, or no medication according to the clinical symptoms and signs and radiographic features. Results: There were 145 primary molars included in the study. No significant differences in clinical and radiographic success rates were found among primary molars treated by pulpotomy using diode laser, sodium hypochlorite, or no medication, when the teeth were treated by experienced pedodontists and restored with stainless steel crowns. The 2-year clinical success rates for primary molars treated by pulpotomy using diode laser, sodium hypochlorite, or no medication were all 100%. The 2-year radiographic success rates were 90.9%, 100%, and 87.5% for primary molars treated by pulpotomy using diode laser, sodium hypochlorite, or no medication, respectively. However, when the pulpotomy for primary molars was performed by less-experienced residents, a reduced overall success rate from 94% for attending doctors to 58% for residents was found. Conclusion: Operators and final restorations are confounding factors for determining the success rate of primary molars treated by pulpotomy. Pulpotomy with diode laser, sodium hypochlorite, or no medication are all acceptable treatments of choice for coronally infected primary molars