Background:The presence of delayed treatment effects(DTE)is common in immuno-oncology trials.However,conventional trial designs often overlook the potential presence of DTE,which can result in an underestimation of th...Background:The presence of delayed treatment effects(DTE)is common in immuno-oncology trials.However,conventional trial designs often overlook the potential presence of DTE,which can result in an underestimation of the required sample size and loss of statistical power.Conversely,when there is actually no apparent delay in treatment effects,alternative trial designs for addressing DTE may lead to an over-estimation of sample size and unnecessary prolongation of the trial duration.To mitigate this challenge,we propose the use of a DTE predicting(DTEP)model to better guide immuno-oncology trial designs.Methods:The DTEP model was developed and validated using data from 147 pub-lished randomized immuno-oncology trials.The eligible trials were divided into a training set(approximately 75%of the trials)and a test set(approximately 25%).We employed linear discriminant analysis(LDA)to develop the DTEP model for pre-dicting the DTE status using baseline characteristics available at the trial design stage.The receiver operating characteristic(ROC)curve was utilized to assess the ability of the model to distinguish between trials with and without DTE.We further re-conducted the JUPITER-02 trial in a simulation setting,employing three design approaches to assess the potential benefits of utilizing the DTEP model.Results:Baseline characteristics available during the trial design stage,including cancer type,line of treatment,and experimental and control arm regimens were incorporated,and high accuracy in predicting the DTE status in both the training set(area under the operating characteristic curve(AUC),0.79;95%confidence interval(CI),0.71-0.88)and test set(AUC,0.78;95%CI,0.66-0.90)was achieved.Notably,the model successfully predicted the DTE status in two randomized trials among the test sets that were conducted by our team(ESCORT-1st(absence of DTE)and JUPITER-02(presence of DTE)).In silico re-conduct of the JUPITER-02 trial further showed that the statistical power would be markedly improved when trial designs were guided by the DTEP model.Conclusions:The DTEP model can significantly enhance the precision and effectiveness of immuno-oncology trial designs,thereby facilitating the discovery of effective im-munotherapeutics in a more streamlined and expedited manner.展开更多
The concrete arch bridge is a natural and appropriate structural solution,aesthetically pleasing and easily integrated into the environment,especially in mountainous and island areas.However,construction difficulty an...The concrete arch bridge is a natural and appropriate structural solution,aesthetically pleasing and easily integrated into the environment,especially in mountainous and island areas.However,construction difficulty and cost will increase with heavy self-weight when the span enlarges.A potential solution is to use a composite box arch ring with steel web-concrete flange.Taking Wanzhou Yangtze River Bridge(the longest concrete arch bridge in the world with a main span of 420 m)as a prototype,trial designs of a composite box arch with steel webs(including corrugated steel webs and plain steel webs)and concrete flanges were carried out.Comparison of quantities and structural behaviors of the prototype concrete arch with the two trial designed composite arch was presented.It is shown that the selfweight of the composite arch can reduce about 28%and the structures can meet the design requirements,therefore it is possible to use the two composite arches in long span arch bridges.展开更多
Let G be a non-abelian group and let l2(G) be a finite dimensional Hilbert space of all complex valued functions for which the elements of G form the (standard) orthonormal basis. In our paper we prove results concern...Let G be a non-abelian group and let l2(G) be a finite dimensional Hilbert space of all complex valued functions for which the elements of G form the (standard) orthonormal basis. In our paper we prove results concerning G-decorrelated decompositions of functions in l2(G). These G-decorrelated decompositions are obtained using the G-convolution either by the irreducible characters of the group G or by an orthogonal projection onto the matrix entries of the irreducible representations of the group G. Applications of these G-decorrelated decompositions are given to crossover designs in clinical trials, in particular the William’s 6×3?design with 3 treatments. In our example, the underlying group is the symmetric group S3.展开更多
AIM:To present statistical tools to model and optimize the cost of a randomized clinical trial as a function of the stringency of patient inclusion criteria.METHODS: We consider a two treatment, dichotomous outcome tr...AIM:To present statistical tools to model and optimize the cost of a randomized clinical trial as a function of the stringency of patient inclusion criteria.METHODS: We consider a two treatment, dichotomous outcome trial that includes a proportion of patients who are strong responders to the tested intervention. Patients are screened for inclusion using an arbitrary number of test results that are combined into an aggregate suitability score. The screening score is regarded as a diagnostic test for the responsive phenotype, having a specific cutoff value for inclusion and a particular sensitivity and specificity. The cutoff is a measure of stringency of inclusion criteria. Total cost is modeled as a function of the cutoff value, number of patients screened, the number of patients included, the case occurrence rate, response probabilities for control and experimental treatments, and the trial duration required to produce a statistically significant result with a specified power. Regression methods are developed to estimate relevant model parameters from pilot data in an adaptive trial design. RESULTS: The patient numbers and total cost are strongly related to the choice of the cutoff for inclusion. Clear cost minimums exist between 5.6 and 6.1 on arepresentative 10-point scale of exclusiveness. Potential cost savings for typical trial scenarios range in millions of dollars. As the response rate for controls approaches 50%, the proper choice of inclusion criteria can mean the difference between a successful trial and a failed trial. CONCLUSION: Early formal estimation of optimal inclusion criteria allows planning of clinical trials to avoid high costs, excessive delays, and moral hazards of Type II errors.展开更多
This paper advances the viewpoints and methods of the rapid sample product trial manufacture technique for developing water meter new products by CAD and simulation, computer virtual assembling and optimizing, rapid m...This paper advances the viewpoints and methods of the rapid sample product trial manufacture technique for developing water meter new products by CAD and simulation, computer virtual assembling and optimizing, rapid machining process and measurement etc. as the design and sample product trial manufacture process of water meter new products are long in product development period, and low in product development efficiency in the present time.展开更多
基金supported by the National Natural Science Foundation of China(82003269,82173128,81803327,81930065,and 81903406)the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(2019-I2M-5-036)the Young Faculty Development Project of Sun Yat-sen University(84000-31660002).
文摘Background:The presence of delayed treatment effects(DTE)is common in immuno-oncology trials.However,conventional trial designs often overlook the potential presence of DTE,which can result in an underestimation of the required sample size and loss of statistical power.Conversely,when there is actually no apparent delay in treatment effects,alternative trial designs for addressing DTE may lead to an over-estimation of sample size and unnecessary prolongation of the trial duration.To mitigate this challenge,we propose the use of a DTE predicting(DTEP)model to better guide immuno-oncology trial designs.Methods:The DTEP model was developed and validated using data from 147 pub-lished randomized immuno-oncology trials.The eligible trials were divided into a training set(approximately 75%of the trials)and a test set(approximately 25%).We employed linear discriminant analysis(LDA)to develop the DTEP model for pre-dicting the DTE status using baseline characteristics available at the trial design stage.The receiver operating characteristic(ROC)curve was utilized to assess the ability of the model to distinguish between trials with and without DTE.We further re-conducted the JUPITER-02 trial in a simulation setting,employing three design approaches to assess the potential benefits of utilizing the DTEP model.Results:Baseline characteristics available during the trial design stage,including cancer type,line of treatment,and experimental and control arm regimens were incorporated,and high accuracy in predicting the DTE status in both the training set(area under the operating characteristic curve(AUC),0.79;95%confidence interval(CI),0.71-0.88)and test set(AUC,0.78;95%CI,0.66-0.90)was achieved.Notably,the model successfully predicted the DTE status in two randomized trials among the test sets that were conducted by our team(ESCORT-1st(absence of DTE)and JUPITER-02(presence of DTE)).In silico re-conduct of the JUPITER-02 trial further showed that the statistical power would be markedly improved when trial designs were guided by the DTEP model.Conclusions:The DTEP model can significantly enhance the precision and effectiveness of immuno-oncology trial designs,thereby facilitating the discovery of effective im-munotherapeutics in a more streamlined and expedited manner.
基金This work was supported by the International Science and Technology Cooperation Projects(No.2009DFA72220)Shanghai Post-Doctoral Projects(No.10R21416100).
文摘The concrete arch bridge is a natural and appropriate structural solution,aesthetically pleasing and easily integrated into the environment,especially in mountainous and island areas.However,construction difficulty and cost will increase with heavy self-weight when the span enlarges.A potential solution is to use a composite box arch ring with steel web-concrete flange.Taking Wanzhou Yangtze River Bridge(the longest concrete arch bridge in the world with a main span of 420 m)as a prototype,trial designs of a composite box arch with steel webs(including corrugated steel webs and plain steel webs)and concrete flanges were carried out.Comparison of quantities and structural behaviors of the prototype concrete arch with the two trial designed composite arch was presented.It is shown that the selfweight of the composite arch can reduce about 28%and the structures can meet the design requirements,therefore it is possible to use the two composite arches in long span arch bridges.
文摘Let G be a non-abelian group and let l2(G) be a finite dimensional Hilbert space of all complex valued functions for which the elements of G form the (standard) orthonormal basis. In our paper we prove results concerning G-decorrelated decompositions of functions in l2(G). These G-decorrelated decompositions are obtained using the G-convolution either by the irreducible characters of the group G or by an orthogonal projection onto the matrix entries of the irreducible representations of the group G. Applications of these G-decorrelated decompositions are given to crossover designs in clinical trials, in particular the William’s 6×3?design with 3 treatments. In our example, the underlying group is the symmetric group S3.
文摘AIM:To present statistical tools to model and optimize the cost of a randomized clinical trial as a function of the stringency of patient inclusion criteria.METHODS: We consider a two treatment, dichotomous outcome trial that includes a proportion of patients who are strong responders to the tested intervention. Patients are screened for inclusion using an arbitrary number of test results that are combined into an aggregate suitability score. The screening score is regarded as a diagnostic test for the responsive phenotype, having a specific cutoff value for inclusion and a particular sensitivity and specificity. The cutoff is a measure of stringency of inclusion criteria. Total cost is modeled as a function of the cutoff value, number of patients screened, the number of patients included, the case occurrence rate, response probabilities for control and experimental treatments, and the trial duration required to produce a statistically significant result with a specified power. Regression methods are developed to estimate relevant model parameters from pilot data in an adaptive trial design. RESULTS: The patient numbers and total cost are strongly related to the choice of the cutoff for inclusion. Clear cost minimums exist between 5.6 and 6.1 on arepresentative 10-point scale of exclusiveness. Potential cost savings for typical trial scenarios range in millions of dollars. As the response rate for controls approaches 50%, the proper choice of inclusion criteria can mean the difference between a successful trial and a failed trial. CONCLUSION: Early formal estimation of optimal inclusion criteria allows planning of clinical trials to avoid high costs, excessive delays, and moral hazards of Type II errors.
文摘This paper advances the viewpoints and methods of the rapid sample product trial manufacture technique for developing water meter new products by CAD and simulation, computer virtual assembling and optimizing, rapid machining process and measurement etc. as the design and sample product trial manufacture process of water meter new products are long in product development period, and low in product development efficiency in the present time.
