A Comparison of Additional Benefit Assessment Methods for Time-to-Event Endpoints Using Hazard Ratio Point Estimates or Confidence Interval Limits by Means of a Simulation Study.

BACKGROUND: For time-to-event endpoints, three additional benefit assessment methods have been developed aiming at an unbiased knowledge about the magnitude of clinical benefit of newly approved treatments. The American Society of Clinical Oncology (ASCO) defines a continuous score using the hazard ratio point estimate (HR-PE). The European Society for Medical Oncology (ESMO) and the German Institute for Quality and Efficiency in Health Care (IQWiG) developed methods with an ordinal outcome using lower and upper limits of the 95% HR confidence interval (HR-CI), respectively. We describe all three frameworks for additional benefit assessment aiming at a fair comparison across different stakeholders. Furthermore, we determine which ASCO score is consistent with which ESMO/IQWiG category. METHODS: In a comprehensive simulation study with different failure time distributions and treatment effects, we compare all methods using Spearman's correlation and descriptive measures. For determination of ASCO values consistent with categories of ESMO/IQWiG, maximizing weighted Cohen's Kappa approach was used. RESULTS: Our research depicts a high positive relationship between ASCO/IQWiG and a low positive relationship between ASCO/ESMO. An ASCO score smaller than 17, 17 to 20, 20 to 24, and greater than 24 corresponds to ESMO categories. Using ASCO values of 21 and 38 as cutoffs represents IQWiG categories. LIMITATIONS: We investigated the statistical aspects of the methods and hence implemented slightly reduced versions of all methods. CONCLUSIONS: IQWiG and ASCO are more conservative than ESMO, which often awards the maximal category independent of the true effect and is at risk of overcompensating with various failure time distributions. ASCO has similar characteristics as IQWiG. Delayed treatment effects and underpowered/overpowered studies influence all methods in some degree. Nevertheless, ESMO is the most liberal one. HIGHLIGHTS: For the additional benefit assessment, the American Society of Clinical Oncology (ASCO) uses the hazard ratio point estimate (HR-PE) for their continuous score. In contrast, the European Society for Medical Oncology (ESMO) and the German Institute for Quality and Efficiency in Health Care (IQWiG) use the lower and upper 95% HR confidence interval (HR-CI) to specific thresholds, respectively. ESMO generously assigns maximal scores, while IQWiG is more conservative.This research provides the first comparison between IQWiG and ASCO and describes all three frameworks for additional benefit assessment aiming for a fair comparison across different stakeholders. Furthermore, thresholds for ASCO consistent with ESMO and IQWiG categories are determined, enabling a comparison of the methods in practice in a fair manner.IQWiG and ASCO are the more conservative methods, while ESMO awards high percentages of maximal categories, especially with various failure time distributions. ASCO has similar characteristics as IQWiG. Delayed treatment effects and under/-overpowered studies influence all methods. Nevertheless, ESMO is the most liberal one. An ASCO score smaller than 17, 17 to 20, 20 to 24, and greater than 24 correspond to the categories of ESMO. Using ASCO values of 21 and 38 as cutoffs represents categories of IQWiG.

Empathy and psychopathology in children and adolescents: the role of parental mental illness and emotion regulation.

Objective: Although empathy is known to be a strength, recent studies suggest that empathy can be a risk factor for psychopathology under certain conditions in children. This study examines parental mental illness as such a condition. Further, it aims to investigate whether maladaptive emotion regulation (ER) mediates the relationship between empathy and psychopathological symptoms of children. Methods: Participants were 100 children of parents with a mental illness (55% female) and 87 children of parents without a mental illness (50% female) aged 6 - 16 years and their parents. Results: Greater cognitive empathy was related to more psychopathological symptoms in COPMI, but not in COPWMI. In addition, in COPMI maladaptive ER mediated this relationship. In contrast, greater affective empathy was associated with more psychopathological symptoms regardless of whether parents had a mental illness. Conclusion: Our findings highlight the importance of implementing preventive programs for COPMI that specifically target the reduction of maladaptive ER.

Bright light therapy versus physical exercise to prevent co-occurring depression in adolescents and young adults with attention-deficit/hyperactivity disorder: a multicentre, three-arm, randomised controlled, pilot phase-IIa trial.

Depression is common in attention-deficit/hyperactivity disorder (ADHD), but preventive behavioural interventions are lacking. This randomised controlled, pilot phase-IIa trial aimed to study a physical exercise intervention (EI) and bright light therapy (BLT)-both implemented and monitored in an individual, naturalistic setting via a mobile health (m-health) system-for feasibility of trial design and interventions, and to estimate their effects on depressive symptoms in young people with ADHD. Two hundred seven participants aged 14-45 years were randomised to 10-week add-on intervention of either BLT (10,000 lx; daily 30-min sessions) (n = 70), EI (aerobic and muscle-strengthening activities 3 days/ week) (n = 69), or treatment-as-usual (TAU) (n = 68), of whom 165 (80%) were retained (BLT: n = 54; EI: n = 52; TAU: n = 59). Intervention adherence (i.e. ≥ 80% completed sessions) was very low for both BLT (n = 13, 22%) and EI (n = 4, 7%). Usability of the m-health system to conduct interventions was limited as indicated by objective and subjective data. Safety was high and comparable between groups. Changes in depressive symptoms (assessed via observer-blind ratings, Inventory of Depressive Symptomatology) between baseline and end of intervention were small (BLT: -0.124 [95% CI: -2.219, 1.971], EI: -2.646 [95% CI: -4.777, -0.515], TAU: -1.428 [95% CI: -3.381, 0.526]) with no group differences [F(2,153) = 1.45, p = 0.2384]. These findings suggest that the m-health approach did not achieve feasibility of EI and BLT in young people with ADHD. Prior to designing efficacy studies, strategies how to achieve high intervention adherence should be specifically investigated in this patient group. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03371810, 13 December 2017.

Optimal sample size allocation for two-arm superiority and non-inferiority trials with binary endpoints.

The sample size of a clinical trial has to be large enough to ensure sufficient power for achieving the aim the study. On the other side, for ethical and economical reasons it should not be larger than necessary. The sample size allocation is one of the parameters that influences the required total sample size. For two-arm superiority and non-inferiority trials with binary endpoints, we performed extensive computations over a wide range of scenarios to determine the optimal allocation ratio that minimizes the total sample size if all other parameters are fixed. The results demonstrate, that for both superiority and non-inferiority trials the optimal allocation may deviate considerably from the case of equal sample size in both groups. However, the saving in sample size when allocating the total sample size optimally as compared to balanced allocation is typically small.

Point estimation, confidence intervals, and P-values for optimal adaptive two-stage designs with normal endpoints.

Due to the dependency structure in the sampling process, adaptive trial designs create challenges in point and interval estimation and in the calculation of P-values. Optimal adaptive designs, which are designs where the parameters governing the adaptivity are chosen to maximize some performance criterion, suffer from the same problem. Various analysis methods which are able to handle this dependency structure have already been developed. In this work, we aim to give a comprehensive summary of these methods and show how they can be applied to the class of designs with planned adaptivity, of which optimal adaptive designs are an important member. The defining feature of these kinds of designs is that the adaptive elements are completely prespecified. This allows for explicit descriptions of the calculations involved, which makes it possible to evaluate different methods in a fast and accurate manner. We will explain how to do so, and present an extensive comparison of the performance characteristics of various estimators between an optimal adaptive design and its group-sequential counterpart.

Primary Tumor Resection Before Systemic Therapy in Patients With Colon Cancer and Unresectable Metastases: Combined Results of the SYNCHRONOUS and CCRe-IV Trials.

PURPOSE: Chemotherapy is established as primary treatment in patients with stage IV colorectal cancer and unresectable metastases. Data from nonrandomized clinical trials have fueled persistent uncertainty if primary tumor resection (PTR) before chemotherapy prolongs survival. We investigated the prognostic value of PTR in patients with newly diagnosed stage IV colon cancer who were not amenable to curative treatment. PATIENTS AND METHODS: Patients enrolled in the multicenter, randomized SYNCHRONOUS and CCRe-IV trials were included in the analysis. Patients with colon cancer with synchronous unresectable metastases were randomly assigned at 100 sites in Austria, Germany, and Spain to undergo PTR or up-front chemotherapy (No PTR group). The chemotherapy regimen was left at discretion of the local team. Patients with tumor-related symptoms, inability to tolerate surgery and/or systemic chemotherapy, and history of another cancer were excluded. The primary end point was overall survival (OS), and the analyses were performed with intention-to-treat. RESULTS: A total of 393 patients were randomly assigned to undergo PTR (n = 187) or no PTR (n = 206) between November 2011 and March 2017. Chemotherapy was not administered to 6.4% in the No PTR group and 24.1% in the PTR group. The median follow-up time was 36.7 months (95% CI, 36.6 to 37.3). The median OS was 16.7 months (95% CI, 13.2 to 19.2) in the PTR group and 18.6 months (95% CI, 16.2 to 22.3) in the No PTR group (P = .191). Comparable OS between the study groups was further confirmed on multivariate analysis (hazard ratio, 0.944 [95% CI, 0.738 to 1.209], P = .65) and across all subgroups. Patients with serious adverse events were more common in the No PTR group (10.2% v 18.0%; P = .027). CONCLUSION: Among patients with colon cancer and synchronous unresectable metastases, PTR before systemic chemotherapy was not associated with prolonged OS.

Randomized phase III GnG study on two schedules of gemtuzumab ozogamicin as adjunct to intensive induction therapy and double-blinded intensive post-remission therapy with or without glasdegib in patients with newly diagnosed acute myeloid leukemia.

Not available.

Parenting stress in parents with and without a mental illness and its relationship to psychopathology in children: a multimodal examination.

Objective: Children of parents with a mental illness are at heightened risk to develop a mental illness themselves due to genetics and environmental factors. Although parenting stress (PS) is known to be associated with increased psychopathology in parents and children, there is no study investigating PS multimodally in a sample of parents with a mental illness. This study aims to compare PS of parents with and without a mental illness and further to examine the relationship between PS and psychopathology of children. Methods: Participants were parents with a mental illness and parents without a mental illness and their children aged four to sixteen years. We assessed PS multimodally using a questionnaire, parents' evaluation of children's behavior (relational schemas) and psychophysiological arousal of parents during free speech task. Results: Self-reported PS was increased, and evaluation of children's behavior was more negative and less positive in parents with a mental illness compared to parents without a mental illness. Children's psychopathology was associated with self-reported PS and relational schemas of parents. Regarding psychophysiological arousal, parents with a mental illness showed reduced reactivity in heart rate from baseline to free speech task in comparison to parents without a mental illness. Conclusions: Our findings highlight the importance of implementing intervention programs to reduce PS for parents and children. In particular, parents with a mental illness might benefit from specific intervention programs in order to interrupt the transgenerational transmission of mental disorders.

Use of class IC antiarrhythmic drugs in patients with structural heart disease and implantable cardioverter defibrillator.

BACKGROUND: Due to suspected pro-arrhythmic effects and increased mortality associated with class-IC antiarrhythmic drugs (AADs) in previous trials, AAD therapy in structural heart disease (SHD) is mainly restricted to amiodarone. In the presence of diagnostic and therapeutic advancements in cardiovascular medicine, it remains unclear if previous studies adequately reflect contemporary patients. In clinical practice, class-IC-AADs are occasionally used in individual cases, particularly in patients with an implantable cardioverter defibrillator (ICD). METHODS: This study retrospectively investigated outcome in ICD-carriers with SHD in whom class-IC-AADs were used as an individualized therapy due to failure, side effects, or unacceptable risk of alternative therapeutic options. RESULTS: Fifty patients from four tertiary centers were included (median age 48.5 years; 52% female). The most common underlying SHD were dilated (42%) or ischemic cardiomyopathy (26%) (median LVEF = 45%). Indications for AAD were sustained ventricular arrhythmias (VA) (58%), symptomatic premature ventricular contractions (26%), or atrial arrhythmias (16%). Median follow-up was 27.8 months. Freedom from sustained VA was 72%, and freedom from ICD therapy was 80%. In 19 patients (38%), AAD therapy was terminated. The most common reason was insufficient efficacy (n = 8). Pro-arrhythmia was suspected in three patients. Five patients died during follow-up (10.0%), two of cardiovascular cause (4.0%). CONCLUSION: In a multicenter cohort of ICD-carriers with SHD, class-IC-AADs were associated with a low rate of pro-arrhythmic effects or cardiovascular mortality. The majority of patients remained free from sustained VA during a follow-up of > 2 years. Further efforts should be made to evaluate the safety of class-IC-AADs in SHD patients receiving contemporary cardiovascular therapy.

Extension of a conditional performance score for sample size recalculation rules to the setting of binary endpoints.

BACKGROUND: Sample size calculation is a central aspect in planning of clinical trials. The sample size is calculated based on parameter assumptions, like the treatment effect and the endpoint's variance. A fundamental problem of this approach is that the true distribution parameters are not known before the trial. Hence, sample size calculation always contains a certain degree of uncertainty, leading to the risk of underpowering or oversizing a trial. One way to cope with this uncertainty are adaptive designs. Adaptive designs allow to adjust the sample size during an interim analysis. There is a large number of such recalculation rules to choose from. To guide the choice of a suitable adaptive design with sample size recalculation, previous literature suggests a conditional performance score for studies with a normally distributed endpoint. However, binary endpoints are also frequently applied in clinical trials and the application of the conditional performance score to binary endpoints is not yet investigated. METHODS: We extend the theory of the conditional performance score to binary endpoints by suggesting a related one-dimensional score parametrization. We moreover perform a simulation study to evaluate the operational characteristics and to illustrate application. RESULTS: We find that the score definition can be extended without modification to the case of binary endpoints. We represent the score results by a single distribution parameter, and therefore derive a single effect measure, which contains the difference in proportions [Formula: see text] between the intervention and the control group, as well as the endpoint proportion [Formula: see text] in the control group. CONCLUSIONS: This research extends the theory of the conditional performance score to binary endpoints and demonstrates its application in practice.

START NOW: a cognitive behavioral skills training for adolescent girls with conduct or oppositional defiant disorder - a randomized clinical trial.

BACKGROUND: Conduct disorder (CD) and oppositional defiant disorder (ODD) both convey a high risk for maladjustment later in life and are understudied in girls. Here, we aimed at confirming the efficacy of START NOW, a cognitive-behavioral, dialectical behavior therapy-oriented skills training program aiming to enhance emotion regulation skills, interpersonal and psychosocial adjustment, adapted for female adolescents with CD or ODD. METHODS: A total of 127 girls were included in this prospective, cluster randomized, multi-center, parallel group, quasi-randomized, controlled phase III trial, which tested the efficacy of START NOW (n = 72) compared with standard care (treatment as usual, TAU, n = 55). All female adolescents had a clinical diagnosis of CD or ODD, were 15.6 (±1.5) years on average (range: 12-20 years), and were institutionalized in youth welfare institutions. The two primary endpoints were the change in number of CD/ODD symptoms between (1) baseline (T1) and post-treatment (T3), and (2) between T1 and 12-week follow-up (T4). RESULTS: Both treatment groups showed reduced CD/ODD symptoms at T3 compared with T1 (95% CI: START NOW = -4.87, -2.49; TAU = -4.94, -2.30). There was no significant mean difference in CD/ODD symptom reduction from T1 to T3 between START NOW and TAU (-0.056; 95% CI = -1.860, 1.749; Hedge's g = -0.011). However, the START NOW group showed greater mean symptom reduction from T1 to T4 (-2.326; 95% CI = -4.274, -0.378; Hedge's g = -0.563). Additionally, secondary endpoint results revealed a reduction in staff reported aggression and parent-reported irritability at post assessment. CONCLUSIONS: Although START NOW did not result in greater symptom reduction from baseline to post-treatment compared with TAU, the START NOW group showed greater symptom reduction from baseline to follow-up with a medium effect size, which indicates a clinically meaningful delayed treatment effect.

Outcome analysis for patients with subarachnoid hemorrhage and vasospasm including endovascular treatment.

As a complication of subarachnoid hemorrhage (SAH), vasospasm substantially contributes to its morbidity and mortality. We aimed at analyzing predictors of outcome for these patients including the role of endovascular treatment (ET). Our database was screened for patients with SAH treated in our Neuro-ICU from 2009 to 2019. Clinical parameters including functional outcome (modified Rankin Scale, mRS of 0-2 or 3-6 at discharge and after a median follow-up of 18 months) and details about ET were gathered on 465 patients, 241 (52%) of whom experienced vasospasm. Descriptive analyses were performed to identify explanatory variables for the dichotomized mRS score. A logistic regression model was fitted on 241 patients with vasospasm including age, Hunt and Hess Score, extraventricular drainage (EVD), forced hypertension, ET and delayed cerebral ischemia (DCI). The model found a Hunt and Hess Score of 5 (OR = 0.043, p = 0.008), requirement of EVD (OR = 0.161, p < 0.001), forced hypertension (OR = 0.242, p = 0.001), ET (OR = 0.431, p = 0.043) and DCI (OR = 0.229, p < 0.001) to be negative predictors of outcome while age was not. Use of intraarterial nimodipine alone (OR = 0.778, p = 0.705) or including balloon angioplasty (OR = 0.894, p = 0.902) and number of ETs per patient (OR = 0.757, p = 0.416) were not significant in a separate model with otherwise identical variables. While DCI is clearly associated with poor outcome, the influence of ET on outcome remains inconclusive. Limited by their retrospective nature and an indication bias, these data encourage a randomized assessment of ET.

Estimation of treatment effects in early-phase randomized clinical trials involving external control data.

There are good reasons to perform a randomized controlled trial (RCT) even in early phases of clinical development. However, the low sample sizes in those settings lead to high variability of the treatment effect estimate. The variability could be reduced by adding external control data if available. For the common setting of suitable subject-level control group data only available from one external (clinical trial or real-world) data source, we evaluate different analysis options for estimating the treatment effect via hazard ratios. The impact of the external control data is usually guided by the level of similarity with the current RCT data. Such level of similarity can be determined via outcome and/or baseline covariate data comparisons. We provide an overview over existing methods, propose a novel option for a combined assessment of outcome and baseline data, and compare a selected set of approaches in a simulation study under varying assumptions regarding observable and unobservable confounder distributions using a time-to-event model. Our various simulation scenarios also reflect the differences between external clinical trial and real-world data. Data combinations via simple outcome-based borrowing or simple propensity score weighting with baseline covariate data are not recommended. Analysis options which conflate outcome and baseline covariate data perform best in our simulation study.

Effect of Individualized Versus Standardized Blood Pressure Management During Endovascular Stroke Treatment on Clinical Outcome: A Randomized Clinical Trial.

BACKGROUND: Optimal blood pressure (BP) management during endovascular stroke treatment is not well established. We studied whether an individualized approach for managing BP during endovascular stroke treatment gives a better clinical outcome than an approach with standardized systolic BP targets. METHODS: The INDIVIDUATE study (Individualized Blood Pressure Management During Endovascular Treatment of Acute Ischemic Stroke Under Procedural Sedation) is a randomized clinical trial with a prospective randomized open blinded end point (PROBE) design. Patients were recruited between October 1, 2020 and July 7, 2022 at a single center at a tertiary care university hospital. Patients were eligible, when they were suffering from acute ischemic stroke of the anterior circulation with occlusions of the internal carotid artery and middle cerebral artery and a National Institutes of Health Stroke Scale score of ≥8 receiving endovascular stroke treatment in procedural sedation. The intervention consists of an individualized BP management strategy, where preinterventional baseline systolic BP (SBP) values are used as intraprocedural BP targets. As a control, the standard treatment aims to maintain the intraprocedural SBP between 140 and 180 mm Hg. The main prespecified outcome is the proportion of favorable functional outcomes 90 days after stroke, defined as a modified Rankin Scale score of 0 to 2. RESULTS: Two hundred fifty patients were enrolled and included in the analysis, mean (SD) age was 77 (12) years, 142 (57%) patients were women, and mean (SD) National Institutes of Health Stroke Scale score on admission was 17 (5.2). In all, 123 (49%) patients were treated with individualized and 127 (51%) with standard BP management. Mean (SD) intraprocedural SBP was similar in the individualized versus standard BP management group (157 [19] versus 154 [18] mm Hg; P=0.16). The rate of favorable functional outcome after 3 months was not significantly different between the individualized versus the standard BP management group (25% versus 24%; adjusted odds ratio, 0.81 [95% CI, 0.41-1.61]; P=0.56). CONCLUSIONS: Among patients treated with endovascular stroke treatment due to an acute ischemic stroke of the anterior circulation, no significant difference was seen between the individualized BP management strategy, where intraprocedural SBP was targeted to baseline values, and the standardized regimen of targeting SBP between 140 and 180 mm Hg. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04578288.

Q-HAM: a multicenter upfront randomized phase II trial of quizartinib and high-dose Ara-C plus mitoxantrone in relapsed/refractory AML with FLT3-ITD.

BACKGROUND: About 50% of older patients with acute myeloid leukemia (AML) fail to attain complete remission (CR) following cytarabine plus anthracycline-based induction therapy. Salvage chemotherapy regimens are based on high-dose cytarabine (HiDAC), which is frequently combined with mitoxantrone (HAM regimen). However, CR rates remain low, with less than one-third of the patients achieving a CR. FLT3-ITD has consistently been identified as an unfavorable molecular marker in both relapsed and refractory (r/r)-AML. One-quarter of patients who received midostaurin are refractory to induction therapy and relapse rate at 2 years exceeds 40%. The oral second-generation bis-aryl urea tyrosine kinase inhibitor quizartinib is a very selective FLT3 inhibitor, has a high capacity for sustained FLT3 inhibition, and has an acceptable toxicity profile. METHODS: In this multicenter, upfront randomized phase II trial, all patients receive quizartinib combined with HAM (cytarabine 3g/m2 bidaily day one to day three, mitoxantrone 10mg/m2 days two and three) during salvage therapy. Efficacy is assessed by comparison to historical controls based on the matched threshold crossing approach with achievement of CR, complete remission with incomplete hematologic recovery (CRi), or complete remission with partial recovery of peripheral blood counts (CRh) as primary endpoint. During consolidation therapy (chemotherapy and allogeneic hematopoietic cell transplantation), patients receive either prophylactic quizartinib therapy or measurable residual disease (MRD)-triggered preemptive continuation therapy with quizartinib according to up-front randomization. The matched threshold crossing approach is a novel study-design to enhance the classic single-arm trial design by including matched historical controls from previous clinical studies. It overcomes common disadvantages of single-armed and small randomized studies, since the expected outcome of the observed study population can be adjusted based on the matched controls with a comparable distribution of known prognostic and predictive factors. Furthermore, balanced treatment groups lead to stable statistical models. However, one of the limitations of our study is the inability to adjust for unobserved or unknown confounders. Addressing the primary endpoint, CR/CRi/CRh after salvage therapy, the maximal sample size of 80 patients is assessed generating a desirable power of the used adaptive design, assuming a logistic regression is performed at a one-sided significance level α=0.05, the aspired power is 0.8, and the number of matching partners per intervention patient is at least 1. After enrolling 20 patients, the trial sample size will be recalculated in an interim analysis based on a conditional power argument. CONCLUSION: Currently, there is no commonly accepted standard for salvage chemotherapy treatment. The objective of the salvage therapy is to reduce leukemic burden, achieve the best possible remission, and perform a hemopoietic stem-cell transplantation. Thus, in patients with FLT3-ITD mutation, the comparison of quizartinib with intensive salvage therapy versus chemotherapy alone appears as a logical consequence in terms of efficacy and safety. ETHICS AND DISSEMINATION: Ethical approval and approvals from the local and federal competent authorities were granted. Trial results will be reported via peer-reviewed journals and presented at conferences and scientific meetings. TRIAL REGISTRATION: ClinicalTrials.gov NCT03989713; EudraCT Number: 2018-002675-17.

Using real-world data to predict health outcomes-The prediction design: Application and sample size planning.

The gold standard for investigating the efficacy of a new therapy is a (pragmatic) randomized controlled trial (RCT). This approach is costly, time-consuming, and not always practicable. At the same time, huge quantities of available patient-level control condition data in analyzable format of (former) RCTs or real-world data (RWD) are neglected. Therefore, alternative study designs are desirable. The design presented here consists of setting up a prediction model for determining treatment effects under the control condition for future patients. When a new treatment is intended to be tested against a control treatment, a single-arm trial for the new therapy is conducted. The treatment effect is then evaluated by comparing the outcomes of the single-arm trial against the predicted outcomes under the control condition. While there are obvious advantages of this design compared to classical RCTs (increased efficiency, lower cost, alleviating participants' fear of being on control treatment), there are several sources of bias. Our aim is to investigate whether and how such a design-the prediction design-may be used to provide information on treatment effects by leveraging external data sources. For this purpose, we investigated under what assumptions linear prediction models could be used to predict the counterfactual of patients precisely enough to construct a test and an appropriate sample size formula for evaluating the average treatment effect in the population of a new study. A user-friendly R Shiny application (available at: https://web.imbi.uni-heidelberg.de/PredictionDesignR/) facilitates the application of the proposed methods, while a real-world application example illustrates them.

A Bayesian approach to clinical trial designs in dermatology with multiple simultaneous treatments per subject and multiple raters.

We consider the statistical analysis of clinical trial designs with multiple simultaneous treatments per subject and multiple raters. The work is motivated by a clinical research project in dermatology where different hair removal techniques were assessed based on a within-subject comparison. We assume that clinical outcomes are assessed by multiple raters as continuous or categorical scores, e.g. based on images, comparing two treatments on the subject-level in a pairwise manner. In this setting, a network of evidence on relative treatment effects is generated, which bears strong similarities to the data underlying a network meta-analysis of clinical trials. We therefore build on established methodology for complex evidence synthesis and propose a Bayesian approach to estimate relative treatment effects and to rank the treatments. The approach is, in principle, applicable to situations with any number of treatment arms and/or raters. As a major advantage, all available data is brought into a network and analyzed in one single model, which ensures consistent results among the treatment comparisons. We obtain operating characteristics via simulation and illustrate the method with a real clinical trial example.

Subtyping of hepatocellular adenomas using Gd-EOB-DTPA: a qualitative and quantitative analysis.

BACKGROUND: The goal of medical imaging is not only to identify the entity "hepatocellular adenoma," but to detect typical magnetic resonance (MR) patterns of the subtypes so that lesions with a higher malignant transformation rate could be differentiated from those that should just be controlled. PURPOSE: To evaluate the differentiation between subtypes of hepatocellular adenomas using hepatobiliary specific contrast agent (Gd-EOB-DTPA) in MR imaging. MATERIAL/METHODS: A total of 11 patients with 39 lesions with histologically proven hepatocellular adenomas were evaluated. Of the, 34 were inflammatory hepatocellular adenomas (IHCA) and 5 were HNF1α adenomas. No ß-catenin-mutated adenoma was found. In all patients, a standard protocol considering the guidelines of the international consensus conference of Gd-EOB-DTPA was performed in a 1.5-T scanner. Besides a qualitative analysis of all sequences, we measured the quantitative signal intensity (SI) ratio in all examinations. RESULTS: Qualitative analysis showed that best sequences for differentiation of HNF1α adenomas from IHCA were T1-weighted (T1W) precontrast (P = 0.03) and portalvenous phase (P < 0.0001) as well as arterial phase (P = 0.002). All adenomas were hypointense in hepatobiliary phase (15 min). The quantitative analyses of the SI ratio and of lesion-to-liver contrast (LLC) ratio show statistically significant differences in T1W precontrast (SI: P = 0.035; LLC: P = 0.049) and portalvenous phase (SI: P = 0.002; LLC: P = 0.002). CONCLUSION: Subtyping of hepatocellular adenomas using Gd-EOB-DTPA is possible due to qualitative and quantitative analyses regarding T1W precontrast and portalvenous phase. In addition, the SI ratio and liver-to-lesion contrast ratio in the arterial phase gave additional qualitative information for differentiation.

Optimization of the two-stage group sequential three-arm gold-standard design for non-inferiority trials.

If design parameters are chosen appropriately, group sequential trial designs are known to be able to reduce the expected sample size under the alternative hypothesis compared to single-stage designs. The same holds true for the so-called 'gold-standard' design for non-inferiority trials, a design involving an experimental group, an active control group, and a placebo group. However, choosing design parameters that maximize the advantages of a two-stage approach for the three-arm gold-standard design for non-inferiority trials is not a straightforward task. In particular, optimal choices of futility boundaries for this design have not been thoroughly discussed in existing literature. We present a variation of the hierarchical testing procedure, which allows for the incorporation of binding futility boundaries at interim analyses. We show that this procedure maintains strong control of the family-wise type I error rate. Within this framework, we consider the futility and efficacy boundaries as well as the sample size allocation ratios as optimization parameters. This allows the investigation of the efficiency gain from including the option to stop for futility in addition to the ability to stop for efficacy. To analyze the extended designs, optimality criteria that include the design's performance under the alternative as well as the null hypothesis are introduced. On top of this, we discuss methods to limit the allocation of placebo patients in the trial while maintaining relatively good operating characteristics. The results of our numerical optimization procedure are discussed and a comparison of different approaches to designing a three-arm gold-standard non-inferiority trial is provided.