Johannes Krisam

Decision Rules for Subgroup Selection Based on a Predictive Biomarker

When investigating a new therapy, there is often some plausibility that the treatment is more efficient (or efficient only) in a subgroup as compared to the total patient population. In this situation, the target population for the proof of efficacy is commonly selected in a data-dependent way, for example, based on the results of a pilot study or a planned interim analysis. The performance of the applied selection rule is crucial for the success of a clinical trial or even a drug development program. We consider the situation in which the selection of the patient population is based on a biomarker and where the diagnostic that evaluates the biomarker may be perfect, that is, with 100% sensitivity and specificity, or not. We develop methods that allow an evaluation of the operational characteristics of rules for selecting the target population, thus enabling the choice of an appropriate strategy. Especially, the proposed procedures can be used to calculate the sample size required to achieve a specified selection probability. Furthermore, we derive optimal selection rules by modeling the uncertainty about parameters by prior distributions. Throughout, there is a strong impact of sensitivity and specificity of the biomarker on the results. It is therefore essential to evaluate the rules for patient selection before applying them, thereby bearing in mind that the diagnostic that evaluates the applied biomarker may be imperfect.

In silico modeling of immunotherapy and stroma-targeting therapies in human colorectal cancer

Despite the fact that the local immunological microenvironment shapes the prognosis of colorectal cancer, immunotherapy has shown no benefit for the vast majority of colorectal cancer patients. A better understanding of the complex immunological interplay within the microenvironment is required. In this study, we utilized wet lab migration experiments and quantitative histological data of human colorectal cancer tissue samples (n = 20) including tumor cells, lymphocytes, stroma, and necrosis to generate a multiagent spatial model. The resulting data accurately reflected a wide range of situations of successful and failed immune surveillance. Validation of simulated tissue outcomes on an independent set of human colorectal cancer specimens (n = 37) revealed the model recapitulated the spatial layout typically found in human tumors. Stroma slowed down tumor growth in a lymphocyte-deprived environment but promoted immune escape in a lymphocyte-enriched environment. A subgroup of tumors with less stroma and high numbers of immune cells showed high rates of tumor control. These findings were validated using data from colorectal cancer patients (n = 261). Low-density stroma and high lymphocyte levels showed increased overall survival (hazard ratio 0.322, P = 0.0219) as compared with high stroma and high lymphocyte levels. To guide immunotherapy in colorectal cancer, simulation of immunotherapy in preestablished tumors showed that a complex landscape with optimal stroma permeabilization and immune cell activation is able to markedly increase therapy response in silico These results can help guide the rational design of complex therapeutic interventions, which target the colorectal cancer microenvironment. Cancer Res; 77(22); 6442-52. ©2017 AACR.

Optimal Decision Rules for Biomarker-Based Subgroup Selection for a Targeted Therapy in Oncology

Throughout recent years, there has been a rapidly increasing interest regarding the evaluation of so-called targeted therapies. These therapies are assumed to show a greater benefit in a pre-specified subgroup of patients—commonly identified by a predictive biomarker—as compared to the total patient population of interest. This situation has led to the necessity to develop biostatistical methods allowing an efficient evaluation of such treatments. Among others, adaptive enrichment designs have been proposed as a solution. These designs allow the selection of the most promising patient population based on an efficacy analysis at interim and restricting recruitment to these patients afterwards. As has recently been shown, the performance of the applied interim decision rule in such a design plays a crucial role in ensuring a successful trial. In this work, we investigate the situation when the primary outcome of the trial is a binary variable. Optimal decision rules are derived which incorporate the uncertainty about the treatment effects. These optimal decision rules are evaluated with respect to their performance in an adaptive enrichment design in terms of correct selection probability and power, and are compared to proposed ad hoc decision rules. Our methods are illustrated by means of a clinical trial example.

Assessing self-management in patients with diabetes mellitus type 2 in Germany: validation of a German version of the Summary of Diabetes Self-Care Activities measure (SDSCA-G)

BackgroundOne of the most widely used self-reporting tools assessing diabetes self-management in English is the Summary of Diabetes Self-Care Activities (SDSCA) measure. To date there is no psychometric validated instrument in German to assess self-management in patients with diabetes mellitus. Therefore, this study aimed to translate the SDSCA into German and examine its psychometric properties.MethodsThe English version of the SDSCA was translated into German following the guidelines for cultural adaptation. The German version of the SDSCA (SDSCA-G) was administered to a random sample of 315 patients with diabetes mellitus type 2. Reliability was analyzed using Cronbach’s alpha coefficient and item characteristics were assessed. Exploratory and confirmatory factor analysis (EFA and CFA) were carried out to explore the construct validity. A multivariable linear regression model was used to identify the influence of predictor variables on the SDSCA-G sum score.ResultsThe Cronbach’s alpha for the SDSCA-G (all items) was α = 0.618 and an acceptable correlation between the SDSCA-G and Self-management Diabetes Mellitus-Questionnaire (SDQ) (ρ = 0.664) was identified. The EFA suggested a four factor construct as did the postulated model. The CFA showed the goodness of fit of the SDSCA-G. However, item 4 was found to be problematic regarding the analysis of psychometric properties. The omission of item 4 yielded an increase in Cronbach’s alpha (α = 0.631) and improvements of the factor structure and model fit. No statistically significant influences of predictor variables on the SDSCA-G sum score were observed.ConclusionThe revised German version of the SDSCA (SDSCA-G) is a reliable and valid tool assessing self-management in adults with type 2 diabetes in Germany.

In vitro investigation on extensively destroyed vital teeth: is fracture force a limiting factor for direct restoration?

To evaluate the in vitro fracture load of extensively damaged vital teeth after either direct or indirect restauration, severe tooth substance loss was simulated for 96 molars. Subsequently, two cavities were prepared with little (design 1) or more substantial (design 2) residual tooth support. All molars were provided with a 2-mm ferrule design and then divided into 12 test groups based on their occlusal surface size. They were restored with composite or with either of two types of single crown (cast metal or milled zirconia). After thermal ageing (10,000 cycles at 6.5 and 60 °C), 1.2 million cycles of chewing simulation were applied (64 N). Maximum fracture load was determined with a loading angle of 45°. Statistical analysis was performed by use of Kaplan-Meier modelling, Students t-tests, one-way anova, post hoc Tukeys HSD tests and linear regression analysis. Regarding mean fracture load without ageing, the indirect restorations outperformed composite (design 1: direct: 508 ± 123 N, indirect: 741 ± 248 N; design 2: direct: 554 ± 167 N, indirect: 903 ± 221 N). After artificial ageing, however, these differences were no longer significant (design 1: direct: 328 ± 189 N, indirect: 506 ± 352 N; design 2: direct 399 ± 208 N, indirect 577 ± 292 N). Instead, the fracture load of the aged composite restorations was comparable with that for zirconia (design 1) and cast metal (design 2) crowns. Fracture loads of direct composite restorations after artificial ageing might fulfil clinical requirements.

Fiber-reinforced composite fixed dental prostheses: A 4-year prospective clinical trial evaluating survival, quality, and effects on surrounding periodontal tissues

Statement of problem. Although fiber‐reinforced composite fixed dental prostheses (FRC FDPs) are a reliable treatment option for the restoration of single missing teeth, comparatively few prospective clinical trials (PCT) exist. Purpose. The purpose of this PCT was to evaluate the survival, quality outcome, and effect of FRC FDPs on periodontal health over 4 years. Material and methods. Twenty‐six consecutive patients (16 men, 10 women) receiving FRC FDPs with preimpregnated unidirectional fiber reinforcement were included in the trial. Eighteen FRC FDPs were placed in the maxilla and 8 in the mandible. Data from baseline, 12‐, 36‐, and 48‐months of follow‐up were recorded, and the prostheses were classified as “success,” “survival,” or “failure.” Periodontal parameters (probing depth, clinical attachment level, plaque index, and bleeding index were assessed, and the quality was rated according to modified United States Public Health Service (USPHS)/Ryge or World Dental Federation (FDI) criteria. Results. Functional survival at 4 years was 73.5% (95% confidence interval [CI], 52.9‐87.3) with 17 FRC FDPs still functioning. Twelve of these were classified as “success” and 5 as “survival.” Overall survival was 53.0% (95% CI, 30.4‐74.4). Six FRC FPDs failed completely. Periodontal parameters did not change over the observation period. Regression analysis showed that probing depth and clinical attachment level did not influence the survival of FRC FDPs. According to USPHS/Ryge/FDI criteria only “wear” and “surface luster” increased significantly over 4 years. Conclusions. The survival rate of FRC FPDs confirms existing data. Negative effects on periodontal health were not seen over the period of observation. Aging effects such as wear were recorded and indicated that FRC FPDs are at risk of disintegration, as they are composed of a fiber framework and veneering composite resin.

Translation and psychometric properties of the German version of the University of the West of England Interprofessional Questionnaire (UWE-IP)

ABSTRACT The implementation of a bachelor degree in Interprofessional Health Care at the University of Heidelberg, Germany, has fostered the need to evaluate the impact of this innovative programme. The University of the West of England Interprofessional Questionnaire (UWE-IP) was developed for longitudinal evaluation of an interprofessional curriculum. The UWE-IP consists of 35 items in four scales: “Communication and Teamwork Scale,” “Interprofessional Learning Scale,” “Interprofessional Interaction Scale,” and “Interprofessional Relationships Scale.” The UWE-IP was translated to German according to international guidelines. Psychometrics were assessed: reliability of the four scales was tested with Cronbach‘s alpha and confirmatory factor analysis was performed to examine the underlying factor structure. The sample consisted of 326 datasets. Reliability for the scales was between 0.75 and 0.90. The underlying factor structure showed a good fit. We conclude that the German UWE-IP shows good psychometrics and recommend its use for evaluation of interprofessional learning activities. These results add to the body of knowledge on evaluation instruments in interprofessional education.

In vitro comparison of the load-bearing capacity of ceramic and metal-ceramic resin-bonded fixed dental prostheses in the posterior region

Statement of problem. The clinical use of ceramic resin‐bonded fixed dental prostheses (RBFDPs) in the posterior region is desirable for esthetic and biological reasons but has been associated with many technical problems, including fractures or chipping of the veneer. Although these problems may be overcome by using monolithic zirconia, information is lacking about the load‐bearing capacity of resin‐bonded monolithic zirconia restorations for replacing a molar. Purpose. The purpose of this in vitro study was to compare the load‐bearing capacity (Fu), the load at initial damage (F1d), and the failure pattern of posterior RBFDPs fabricated from monolithic zirconia (MZr), veneered zirconia (VZr), and veneered cobalt‐chromium (VCo). Material and methods. For the replacement of a maxillary first molar, 4 groups (n=8) of RBFDPs differing in prosthesis material and retainer design (MZr‐IR‐RBFDPs, VZr‐IR‐RBFDPs, MZr‐WR‐RBFDPs, and VCo‐WR‐RBFDPs; IR, inlay‐retained; WR, adhesive wing‐retained) were fabricated with anatomic congruence of the FDP‐abutment complex. The RBFDPs were subjected to thermocycling (10 000×6.5°C/60°C) and mastication simulation (30‐degree oblique loading on the pontic; 1 200 000×108 N) and then loaded until failure in a universal testing machine (0.5 mm/minute). Test forces correlating with Fu and F1d were recorded. Statistical analysis was performed by using 2‐way analysis of variance (ANOVA), 2‐way repeated measures ANOVA, and the Tukey honest significant differences post hoc test (2‐sided &agr;=.05). Results. Fu was significantly affected by retainer design (P<.001) and F1d by both retainer design (P<.001) and prosthesis material (P<.001). Fu was more than 2000 N for WR‐RBFDPs and more than 1000 N for IR‐RBFDPs (Tukey test ranking: MZr‐WR‐RBFDPs = VCo‐WR‐RBFDPs > MZr‐IR‐RBFDPs = VZr‐IR‐RBFDPs). Ceramic RBFDPs failed by complete fracture in the connector region, whereas failure of VCo‐WR‐RBFDPs was limited to the ceramic veneer. F1d was significantly lower (P≤.004) than Fu for veneered specimens only; F1d started at test forces below 500 N and coincided with veneer cracking. Conclusions. Load‐bearing capacity suitable for the definitive restoration of a molar was observed for all groups. Veneered resin‐bonded fixed dental prostheses, however, were susceptible to cracking of the veneer.

Health-Related Quality of Life in Primary Care: Which Aspects Matter in Multimorbid Patients with Type 2 Diabetes Mellitus in a Community Setting?

Background and Objective Knowledge about predictors of health-related quality of life for multimorbid patients with type 2 diabetes mellitus in primary care could help to improve quality and patient-centeredness of care in this specific group of patients. Thus, the aim of this study was to investigate the impact of several patient characteristics on health-related quality of life of multimorbid patients with type 2 diabetes mellitus in a community setting. Research Design and Methods A cross-sectional study with 32 primary care practice teams in Mannheim, Germany, and randomly selected multimorbid patients with type 2 diabetes mellitus (N = 495) was conducted. In order to analyze associations of various patient characteristics with health-related quality of life (EQ-5D index) a multilevel analysis was applied. Results After excluding patients with missing data, the cohort consisted of 404 eligible patients. The final multilevel model highlighted six out of 14 explanatory patient variables which were significantly associated with health-related quality of life: female gender (r = -0.0494; p = .0261), school education of nine years or less (r = -0.0609; p = .0006), (physical) mobility restrictions (r = -0.1074; p = .0003), presence of chronic pain (r = -0.0916; p = .0004), diabetes-related distress (r = -0.0133; p < .0001), and BMI (r = -0.0047; p = .0045). Conclusion The findings of this study suggest that increased diabetes-related distress, chronic pain, restrictions in (physical) mobility, female gender, as well as lower education and, increased BMI have a noteworthy impact on health-related quality of life in multimorbid patients with type 2 diabetes mellitus seen in primary care practices in a community setting. The highlighted aspects should gain much more attention when treating multimorbid patients with type 2 diabetes mellitus.

Generation of a New Disease-specific Prognostic Score for Patients With Brain Metastases From Small-cell Lung Cancer Treated With Whole Brain Radiotherapy (BMS-Score) and Validation of Two Other Indices

&NA; The purpose of this study was to develop a prognostic score for patients with brain metastases from SCLC treated with WBRT (BMS‐score). The new BMS score was more prognostic than the RPA and ds‐GPA score. BMS score and RPA showed the most significant differences between classes. Introduction: Patients with small‐cell lung cancer (SCLC) demonstrate an exception in the treatment of brain metastases (BM), because in patients with SCLC whole brain radiotherapy (WBRT) only is the preferred treatment modality. The purpose of this study was to develop a prognostic score for patients with brain metastases from SCLC treated with WBRT. Patients and Methods: The present study was conducted utilizing a single‐institution, previously described, retrospective database of patients with SCLC who were treated with WBRT (n = 221). Univariate and multivariate analyses were performed to generate the “brain metastases from SCLC score” (BMS score) based on favorable prognostic factors: Karnofsky performance status (KPS > 70), extracerebral disease status (stable disease/controlled), and time of appearance of BM (synchronous). Furthermore, the disease‐specific graded prognostic assessment score as well as the recursive partitioning analysis (RPA) were performed and compared with the new BMS score by using the log‐rank (Mantel‐Cox) test. Results: BMS score and RPA showed the most significant differences between classes (P < .001). BMS score revealed a mean overall survival (OS) of 2.62 months in group I (0‐1 points), 6.61 months in group II (2‐3 points), and 12.31 months in group III (4 points). The BMS score also identified the group with the shortest survival (2.62 months in group I), and the numbers of patients in each group were most equally distributed with the BMS score. Conclusion: The new BMS score was more prognostic than the RPA and disease‐specific graded prognostic assessment scores. The BMS score is easy to use and reflects known prognostic factors in contemporary patients with SCLC treated with WBRT. Future studies are necessary to validate these findings.