Adaptive trial designs in diagnostic accuracy research.

The aim of diagnostic accuracy studies is to evaluate how accurately a diagnostic test can distinguish diseased from nondiseased individuals. Depending on the research question, different study designs and accuracy measures are appropriate. As the prior knowledge in the planning phase is often very limited, modifications of design aspects such as the sample size during the ongoing trial could increase the efficiency of diagnostic trials. In intervention studies, group sequential and adaptive designs are well established. Such designs are characterized by preplanned interim analyses, giving the opportunity to stop early for efficacy or futility or to modify elements of the study design. In contrast, in diagnostic accuracy studies, such flexible designs are less common, even if they are as important as for intervention studies. However, diagnostic accuracy studies have specific features, which may require adaptations of the statistical methods or may lead to specific advantages or limitations of sequential and adaptive designs. In this article, we summarize the current status of methodological research and applications of flexible designs in diagnostic accuracy research. Furthermore, we indicate and advocate future development of adaptive design methodology and their use in diagnostic accuracy trials from an interdisciplinary viewpoint. The term "interdisciplinary viewpoint" describes the collaboration of experts of the academic and nonacademic research.

Analytical and Clinical Validation of a Point-of-Care Cardiac Troponin T Test with an Improved Detection Limit.

BACKGROUND: The point-of-care test Roche CARDIAC POC Troponin T (PoC TnT) is an improved assay which has been developed for the Roche cobas h 232 system. METHODS: We performed a multicentre evaluation (four sites) to assess the analytical performance of the PoC TnT assay and to compare it with the central laboratory Elecsys® troponin T high sensitive (lab cTnT-hs) assay. RESULTS: The relative mean differences found in method comparisons of PoC TnT vs. lab cTnT-hs ranged from -4.1% to +6.8%. Additionally, there was good concordance between PoC TnT and lab cTnT-hs for the number of samples with troponin T values below the measuring range of 40 ng/L. Lot-to-lot differences of PoC TnT ranged from -8.6% to +4.6%. Within-series coefficients of variation (CV) resulting from 81 ten-fold measurements with patient samples were 9.3%, 11.8%, and 12.9% in the low (40 to < 200 ng/L), medium (200 to < 600 ng/L), and high (600 to 2000 ng/L) measuring range, respectively. Using the system quality control, the mean CV for between-day imprecision was 11.3%. No interference was observed by triglycerides (up to 11.4 mmol/L), bilirubin (up to 376 µmol/L), hemoglobin (up to 0.12 mmol/L), biotin (up to 30 µg/L), rheumatoid factor (up to 200 IU/mL), or with 52 standard or cardiovascular drugs at therapeutic concentrations. There was no influence on the results by varying hematocrit values in a range from 25% to 53%. However, interferences with human anti-mouse antibodies were found. No significant influence on the results was found with PoC TnT by using sample volumes between 135 to 165 µL. High troponin T concentrations up to 500 µg/L did not lead to false low results, indicating no high-concentration hook effect. No cross-reactivity was found between the PoC TnT assay and human skeletal troponin T up to 1000 µg/L (< 0.05%). Diagnostic sensitivity and specificity data of a subpopulation (23 patients) of this study are in agreement with results of another large pre-hospital study. CONCLUSIONS: The PoC TnT assay showed good analytical performance with excellent concordance with the calibration and reference laboratory method. It should therefore be suitable for its intended use in point-of-care settings.

Methylthioadenosine phosphorylase represents a predictive marker for response to adjuvant interferon therapy in patients with malignant melanoma.

Using tissue microarrays assembling 465 nevi, primary melanomas and metastases, we investigated whether expression of methylthioadenosine phosphorylase (MTAP), a recently suggested biomarker of malignant melanoma, has prognostic significance and may predict responsiveness to adjuvant interferon therapy in patients with melanoma. Because of its association with MTAP activity and interferon signalling pathways, signal transducer and activator of transcription 1 (STAT1) immunohistochemistry was analysed, too. MTAP expression was significantly reduced in melanomas and metastases compared with nevi (P < 0.001); STAT1 expression significantly increased. In melanomas, loss of MTAP expression was significantly related to Clark level (P < 0.05) and tumor thickness (P < 0.01); whereas STAT1 immunoreactivity was significantly related to gender (p < 0.05) and tumor thickness (P < 0.05). Interestingly, subgroup analysis of patients with a tumor thickness of 1.5-4.0 mm revealed a significant survival benefit from adjuvant interferon treatment regarding recurrence-free survival (RFS; P < 0.05) if MTAP expression was observed in the primary melanoma. Patients with STAT1-positive melanomas also tended to benefit from interferon concerning RFS (P = 0.074) and showed a significant benefit concerning overall survival (OS; P < 0.05). According to Cox analysis, MTAP expression in contrast to STAT1 was an independent positive prognostic marker for RFS and OS. In conclusion, MTAP represents a highly promising immunohistochemical marker for prognosis and interferon response of patients with malignant melanoma.

Quality of life diagnosis and therapy as complex intervention for improvement of health in breast cancer patients: delineating the conceptual, methodological, and logistic requirements (modeling).

BACKGROUND AND AIMS: A system for quality of life (QoL) diagnosis and therapy in breast cancer patients was developed according to the Medical Research Council (MRC) framework of complex interventions. Along MRC's five phases in the continuum of evidence, the present paper deals with phase I: modeling (i.e., delineating the conceptual, methodological, and logistic requirements). BASIC ELEMENTS: Theoretical background is a new conceptualization of QoL that provides a rational basis to diagnose "diseased" QoL. A care pathway as the central part of modeling is composed of the following interrelated structural elements: patients (n = 170), clinicians (n = 10), experts in a quality of life unit (n = 5), coordinating practitioners (n = 38), local opinion leaders (n = 12), and professional therapists for QoL enhancing therapies (n = 75). Networking of these structural elements was achieved by clinical algorithm. In the clinical center, the patient and doctor delivered a questionnaire (EORTC) and health status report. The QoL unit transformed it into a profile and experts' report. The coordinating practitioner transformed the latter into a decision on QoL therapy and the care pathway ended with the professional therapists. Implementation of this system used a multifaceted strategy including educational outreach visits, local opinion leaders, and quality circles. CONCLUSION: The suffering cancer patient is the main focus of this QoL diagnosis and therapy system. It will have to pass the rigorous test of a definitive randomized trial.

[Diagnosis and therapy of illness-related quality of life in breast cancer patients. Protocol of a randomized clinical trial at the Regensburg Tumour Centre]. / Diagnostik und Therapie der krankheitsbezogenen Lebensqualität bei Patientinnen mit Mammakarzi- nom. Protokoll einer randomisierten klinischen Studie am Tumorzentrum Regensburg.

BACKGROUND: The project conducted at the Tumour Centre in Regensburg aims to integrate quality of life (QL) diagnostics with the therapy of breast cancer patients and to evaluate the efficacy of QL diagnostics in the context of a randomized clinical trial. METHODS: The Regensburg Tumour Centre provides the infrastructure of the present project (telemedicine, project groups, quality circle). The treatment of breast cancer patients is based on the recent national breast cancer therapy guideline, including assorted QL-enhancing therapy options such as pain therapy, physiotherapy and lymphatic drainage, psychotherapy, social counselling and rehabilitation, nutrition and sports. During an implementation phase a new method of QL diagnostics has been developed. Five experts with varying professional background use the individual patient's QL profile and clinical and socio-demographic information in order to generate a QL report including a treatment recommendation. The study is designed as a two- arm randomized clinical trial with one test group (communication of the QL findings to the co-ordinating physician) and a control group (no communication). Patients with newly diagnosed breast cancer who are treated in the study region by one of the co-ordinating doctors will be included in this randomized study. At designated points in time QL assessments (EORTC QLQ-C30 plus BR23) will be conducted over a 12-months period. EXPECTED RESULTS: We expect that patients in the test group will experience a lower amount of QL deficits at the end of the study period (M = 1, SD = 2) than patients in the control group (M = 2, SD = 2). The statistical confirmation of this expected effect requires a total sample size of N = 200 (n = 100 vs. n = 100, alpha = 5% [two-tailed], beta = 10%). CONCLUSIONS: This is the first study to evaluate a new form of QL diagnostics in the complexity of a real patient care environment, and it promises to make the inclusion of the quality of life concept into the current breast cancer treatment guideline more tangible.