Discrimination of benign, atypical, and malignant peripheral nerve sheath tumors in neurofibromatosis type 1 using diffusion-weighted MRI.

Background: Neurofibromatosis type 1 (NF1) is associated with the development of benign (BPNST) and malignant (MPNST) peripheral nerve sheath tumors. Recently described atypical neurofibromas (ANF) are considered pre-malignant precursor lesions to MPNSTs. Previous studies indicate that diffusion-weighted magnetic resonance imaging (DW-MRI) can reliably discriminate MPNSTs from BPNSTs. We therefore investigated the diagnostic accuracy of DW-MRI for the discrimination of benign, atypical, and malignant peripheral nerve sheath tumors. Methods: In this prospective explorative single-center phase II diagnostic study, 44 NF1 patients (23 male; 30.1 ±â€…11.8 years) underwent DW-MRI (b-values 0-800 s/mm²) at 3T. Two radiologists independently assessed mean and minimum apparent diffusion coefficients (ADCmean/min) in areas of largest tumor diameters and ADCdark in areas of lowest signal intensity by manual contouring of the tumor margins of 60 BPNSTs, 13 ANFs, and 21 MPNSTs. Follow-up of ≥ 24 months (BPNSTs) or histopathological evaluation (ANFs + MPNSTs) served as diagnostic reference standard. Diagnostic ADC-based cut-off values for discrimination of the three tumor groups were chosen to yield the highest possible specificity while maintaining a clinically acceptable sensitivity. Results: ADC values of pre-malignant ANFs clustered between BPNSTs and MPNSTs. Best BPNST vs. ANF + MPNST discrimination was obtained using ADCdark at a cut-off value of 1.6 × 10-3 mm2/s (85.3% sensitivity, 93.3% specificity), corresponding to an AUC of 94.3% (95% confidence interval: 85.2-98.0). Regarding BPNST + ANF vs. MPNST, best discrimination was obtained using an ADCdark cut-off value of 1.4 × 10-3 mm2/s (83.3% sensitivity, 94.5% specificity). Conclusions: DW-MRI using ADCdark allows specific and noninvasive discrimination of benign, atypical, and malignant nerve sheath tumors in NF1.

A Multimodal Lifestyle Psychosocial Survivorship Program in Young Cancer Survivors: The CARE for CAYA Program-A Randomized Clinical Trial Embedded in a Longitudinal Cohort Study.

Importance: There is a lack of trials examining the effect of counseling interventions for child, adolescent, and younger adult (CAYA) cancer survivors. Objective: To assess lifestyle habits and the psychosocial situation of CAYAs to determine the efficacy of needs-based interventions in the CARE for CAYA program (CFC-P). Design, Setting, and Participants: The CFC-P was conducted as a multicenter program in 14 German outpatient clinics, mainly university cancer centers. Recruitment began January 1, 2018; a randomized clinical trial was conducted until July 15, 2019; and intervention was continued as a longitudinal cohort study until March 31, 2021. Data preparation was conducted from April 1, 2021, and analysis was conducted from August 14, 2021, to May 31, 2022. Herein, predefined confirmatory analyses pertain to the RCT and descriptive results relate to the overall longitudinal study. Data analysis was based on the full analysis set, which is as close as possible to the intention-to-treat principle. Intervention: A comprehensive assessment determined needs in physical activity, nutrition and psychooncology. Those with high needs participated in 1 to 3 modules. In the RCT, the IG received 5 counseling sessions plus newsletters, while the control group CG received 1 counseling session. Main Outcomes and Measures: The primary outcome was the change in the rate of CAYAs with high needs at 52 weeks. Secondary outcomes were feasibility, modular-specific end points, satisfaction, quality of life, and fatigue. Results: Of 1502 approached CAYAs aged 15 to 39 years, 692 declined participation. Another 22 CAYAs were excluded, resulting in 788 participants. In the randomized clinical trial, 359 CAYAs were randomized (intervention group [IG], n = 183; control group [CG], n = 176), and 274 were followed up. In the RCT, the median age was 25.0 (IQR, 19.9-32.2) years; 226 were female (63.0%) and 133 male (37.0%). After 52 weeks, 120 CAYAs (87.0%) in the IG and 115 (86.5%) in the CG still had a high need in at least 1 module (odds ratio, 1.04; 95% CI, 0.51-2.11; P = .91). Both groups reported reduced needs, improved quality of life, reduced fatigue, and high satisfaction with the CFC-P. Conclusions and Relevance: In this randomized clinical trial, the implementation of a lifestyle program in this cohort was deemed necessary, despite not meeting the primary outcome. The interventions did not alter the rate of high needs. The results may provide guidance for the development of multimodal interventions in the follow-up care of CAYAs. Trial Registration: German Clinical Trial Register: DRKS00012504.

A diagnostic phase III/IV seamless design to investigate the diagnostic accuracy and clinical effectiveness using the example of HEDOS and HEDOS II.

The development process of medical devices can be streamlined by combining different study phases. Here, for a diagnostic medical device, we present the combination of confirmation of diagnostic accuracy (phase III) and evaluation of clinical effectiveness regarding patient-relevant endpoints (phase IV) using a seamless design. This approach is used in the Thyroid HEmorrhage DetectOr Study (HEDOS & HEDOS II) investigating a post-operative hemorrhage detector named ISAR-M THYRO® in patients after thyroid surgery. Data from the phase III trial are reused as external controls in the control group of the phase IV trial. An unblinded interim analysis is planned between the two study stages which includes a recalculation of the sample size for the phase IV part after completion of the first stage of the seamless design. The study concept presented here is the first seamless design proposed in the field of diagnostic studies. Hence, the aim of this work is to emphasize the statistical methodology as well as feasibility of the proposed design in relation to the planning and implementation of the seamless design. Seamless designs can accelerate the overall trial duration and increase its efficiency in terms of sample size and recruitment. However, careful planning addressing numerous methodological and procedural challenges is necessary for successful implementation as well as agreement with regulatory bodies.

Non-contrast free-breathing 2D CINE compressed SENSE T1-TFE cardiovascular MRI at 3T in sedated young children for assessment of congenital heart disease.

Cardiac MRI is a crucial tool for assessing congenital heart disease (CHD). However, its application remains challenging in young children when performed at 3T. The aim of this retrospective single center study was to compare a non-contrast free-breathing 2D CINE T1-weighted TFE-sequence with compressed sensing (FB 2D CINE CS T1-TFE) with 3D imaging for diagnostic accuracy of CHD, image quality, and vessel diameter measurements in sedated young children. FB 2D CINE CS T1-TFE was compared with a 3D non-contrast whole-heart sequence (3D WH) and 3D contrast-enhanced MR angiography (3D CE-MRA) at 3T in 37 CHD patients (20♂, 1.5±1.4 years). Two radiologists independently assessed image quality, type of CHD, and diagnostic confidence. Diameters and measures of contrast and sharpness of the aorta and pulmonary vessels were determined. A non-parametric multi-factorial approach was used to estimate diagnostic accuracy for the diagnosis of CHD. Linear mixed models were calculated to compare contrast and vessel sharpness. Krippendorff's alpha was determined to quantify vessel diameter agreement. FB 2D CINE CS T1-TFE was rated superior regarding image quality, diagnostic confidence, and diagnostic sensitivity for both intra- and extracardiac pathologies compared to 3D WH and 3D CE-MRA (all p<0.05). FB 2D CINE CS T1-TFE showed superior contrast and vessel sharpness (p<0.001) resulting in the highest proportion of measurable vessels (740/740; 100%), compared to 3D WH (530/620; 85.5%) and 3D CE-MRA (540/560; 96.4%). Regarding vessel diameter measurements, FB 2D CINE CS T1-TFE revealed the closest inter-reader agreement (Krippendorff's alpha: 0.94-0.96; 3D WH: 0.78-0.94; 3D CE-MRA: 0.76-0.93). FB 2D CINE CS T1-TFE demonstrates robustness at 3T and delivers high-quality diagnostic results to assess CHD in sedated young children. Its ability to function without contrast injection and respiratory compensation enhances ease of use and could encourage widespread adoption in clinical practice.

TGFß level in healthy and children with Marfan syndrome-effective reduction under sartan therapy.

Introduction: Transforming growth factor ß (TGFß) metabolism plays an important role in the pathogenesis of Marfan syndrome (MFS). Accordingly, drug therapy uses TGFß receptor blockade to slow down the cardiovascular manifestations, above all aortic root dilatation. Angiotensin II type 1 receptor blockers (ARBs) have been shown to reduce TGFß levels in adults. Data on childhood are lacking and are now being investigated in the TiGer For Kids study presented here. Methods: We examined 125 children without chronic disease and 31 pediatric Marfan patients with a proven FBN1 variant with regard to TGFß levels. In addition, we measured TGFß levels during the initiation of ARB therapy in pediatric Marfan patients. Results: In children without chronic disease, TGFß levels were found to decrease from childhood to adolescence (p < 0.0125). We could not measure a relevantly increased TGFß level in pediatric Marfan patients. However, we showed a significant suppression of the TGFß level after treatment with ARBs (p < 0.0125) and a renewed increase shortly before the next dose. Discussion: The TGFß level in childhood changes in an age-dependent manner and decreases with age. The TGFß level drops significantly after taking ARBs. Based on our experience and data, a TGFß receptor blockade in childhood seems reasonable. So far, TGFß level cannot be used as an MFS screening biomarker.

Is an intraoperative liver function assessment possible? Application of the 13C-methacetin-breath-test during major liver resections - a pilot study.

BACKGROUND: As prevention of posthepatectomy-liver-failure is crucial, there is need of dynamic assessment of liver function, even intraoperatively. 13C-methacetin-breath-test estimates the organ's microsomal functional capacity. This is its first intraoperative evaluation in major liver surgery. METHODS: 30 patients planed for resection of ≥3 liver segments, between March-November 2019, were prospectively enrolled in this "single-center", pilot study. Using the 13C-methacetin-breath-test, liver function was assessed four times: preoperatively, intraoperatively before and after resection and postoperatively. The resulted maximum-liver-function-capacity (LiMAx)-values and delta-over-baseline (DOB)-curves were compared, further analyzed and correlated to respective liver volumes. RESULTS: The intraoperative LiMAx-values before resection were mostly lower than the preoperative ones (-11.3% ± 28%). The intraoperative measurements after resection resulted to mostly higher values than the postoperative ones (42.35% ± 46.19%). Pharmacokinetically, an interference between the two intraoperative tests was observed. There was no strong correlation between residual liver volume and function with a percentual residual-LiMAx mostly lower than the percentual residual volume (-17.7% ± 4.1%). CONCLUSIONS: Intraoperative application of the 13C-methacetin-breath-test during major liver resections seems to deliver lower values than the standard preoperative test. As multiple intraoperative tests interfere significantly to each other, a single intraoperative measurement is suggested. Multicentric standardized measurements could define the "normal" range for intraoperative measurements and control their predictive value.

Hyperangulated blades or direct epiglottis lifting to optimize glottis visualization in difficult Macintosh videolaryngoscopy: a non-inferiority analysis of a prospective observational study.

Purpose: It is unknown if direct epiglottis lifting or conversion to hyperangulated videolaryngoscopes, or even direct epiglottis lifting with hyperangulated videolaryngoscopes, may optimize glottis visualization in situations where Macintosh videolaryngoscopy turns out to be more difficult than expected. This study aims to determine if the percentage of glottic opening (POGO) improvement achieved by direct epiglottis lifting is non-inferior to the one accomplished by a conversion to hyperangulated videolaryngoscopy in these situations. Methods: One or more optimization techniques were applied in 129 difficult Macintosh videolaryngoscopy cases in this secondary analysis of a prospective observational study. Stored videos were reviewed by at least three independent observers who assessed the POGO and six glottis view grades. A linear mixed regression and a linear regression model were fitted. Estimated marginal means were used to analyze differences between optimization maneuvers. Results: In this study, 163 optimization maneuvers (77 direct epiglottis lifting, 57 hyperangulated videolaryngoscopy and 29 direct epiglottis lifting with a hyperangulated videolaryngoscope) were applied exclusively or sequentially. Vocal cords were not visible in 91.5% of the cases with Macintosh videolaryngoscopy, 24.7% with direct epiglottis lifting, 36.8% with hyperangulated videolaryngoscopy and 0% with direct lifting with a hyperangulated videolaryngoscope. Conversion to direct epiglottis lifting improved POGO (mean + 49.7%; 95% confidence interval [CI] 41.4 to 58.0; p < 0.001) and glottis view (mean + 2.2 grades; 95% CI 1.9 to 2.5; p < 0.001). Conversion to hyperangulated videolaryngoscopy improved POGO (mean + 43.7%; 95% CI 34.1 to 53.3; p < 0.001) and glottis view (mean + 1.9 grades; 95% CI 1.6 to 2.2; p < 0.001). The difference in POGO improvement between conversion to direct epiglottis lifting and conversion to hyperangulated videolaryngoscopy is: mean 6.0%; 95% CI -6.5-18.5%; hence non-inferiority was confirmed. Conclusion: When Macintosh videolaryngoscopy turned out to be difficult, glottis exposure with direct epiglottis lifting was non-inferior to the one gathered by conversion to hyperangulated videolaryngoscopy. A combination of both maneuvers yields the best result. Clinical trial registration: ClinicalTrials.gov, NCT03950934.

Muscle quality determined by computed tomography predicts short-term and long-term survival after liver transplantation.

Sarcopenia, the loss of muscle mass and quality, contributes to worse clinical outcome in patients with end-stage liver disease, but its impact on short- and long-term survival remains insufficiently understood. The aim of this study was to evaluate the development of computed tomography (CT) muscle parameters and their impact on short-term and long-term survival after liver transplantation. This retrospective study included patients with liver transplantation between 2011 and 2015 and a pre-transplant CT scan. Clinical characteristics, CT muscle mass and density were assessed pre-transplant, and in available CT scans at short-term (11 months) and long-term follow-up (56 months). Overall, 93/152 (61%) patients (109 male, 55 ± 10 years) suffered from sarcopenia pre-transplant. In short- (n = 50) and long-term follow-up (n = 52) the muscle mass (- 2.65 cm2/m2 95% CI [- 4.52, - 0.77], p = 0.007; - 2.96 cm2/m2 [- 4.7, - 1.23], p = 0.001, respectively), and muscle density (- 3 HU [- 6, - 1], p = 0.007; - 2 HU [- 4, 0], p = 0.069) decreased. Myosteatosis was associated with a higher post-transplant mortality (survival probability: 3 months 72% vs. 95%, 1 year 63% vs. 90%, 5 years 54% vs. 84%, p = 0.001), while muscle mass was not. In conclusion, muscle mass and quality did not improve after transplant. Muscle quality predicts short- and long-term survival and could help to identify a patient's risk profile.

Transnasal Videoendoscopy for Preoperative Airway Risk Stratification: Development and Validation of a Multivariable Risk Prediction Model.

BACKGROUND: Transnasal flexible videoendoscopy (TVE) of the larynx is a standard of care for the detection and staging of pharyngolaryngeal lesions in otorhinolaryngology. Patients frequently present with existing TVE examinations before anesthesia. Although these patients are considered high risk, the diagnostic value of TVE for airway risk stratification is currently unknown. How can captured images or videos be used for anesthesia planning, and which lesions are most concerning? This study aimed to develop and validate a multivariable risk prediction model for difficult airway management based on TVE findings and to determine whether the discrimination of the Mallampati score can be improved by adding this new TVE model. METHODS: This retrospective single-center development and validation study assessed 4021 patients who underwent 4524 otorhinolaryngologic surgeries at the University Medical Centre Hamburg-Eppendorf between January 1, 2011, and April 30, 2018, with electronically stored TVE videos and included 1099 patients who underwent 1231 surgeries. TVE videos and anesthesia charts were systematically reviewed in a blinded fashion. The Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis was used for variable selection, model development, and cross validation. RESULTS: The prevalence of difficult airway management was 24.7% (304/1231). Lesions at the vocal cords, epiglottis, or hypopharynx were not selected by the LASSO regression, while lesions at the vestibular folds (ß-coefficient 0.123), supraglottic region (ß-coefficient 0.161), arytenoids (ß-coefficient 0.063), and viewing restrictions on the rima glottidis that cover ≥50% of the glottis area (ß-coefficient 0.485) and pharyngeal secretion retention (ß-coefficient 0.372) were relevant risk factors for difficult airway management. The model was adjusted for sex, age, and body mass index. The area under the receiver operating characteristic curve (95% confidence interval) of the Mallampati score was 0.61 (0.57-0.65) and 0.74 (0.71-0.78) of the TVE model combined with Mallampati ( P < .001). CONCLUSIONS: Stored images and videos from TVE examinations can be reused for the purpose of predicting risk associated with airway management. Vestibular fold, supraglottic, and arytenoid lesions are most concerning, especially if they are accompanied by secretion retention or restrict the glottic view. Our data indicate that the TVE model improves discrimination of the Mallampati score and might, therefore, be a useful addition to traditional bedside airway risk examinations.

Noninferiority of Artificial Intelligence-Assisted Analysis of Ki-67 and Estrogen/Progesterone Receptor in Breast Cancer Routine Diagnostics.

Image analysis assistance with artificial intelligence (AI) has become one of the great promises over recent years in pathology, with many scientific studies being published each year. Nonetheless, and perhaps surprisingly, only few image AI systems are already in routine clinical use. A major reason for this is the missing validation of the robustness of many AI systems: beyond a narrow context, the large variability in digital images due to differences in preanalytical laboratory procedures, staining procedures, and scanners can be challenging for the subsequent image analysis. Resulting faulty AI analysis may bias the pathologist and contribute to incorrect diagnoses and, therefore, may lead to inappropriate therapy or prognosis. In this study, a pretrained AI assistance tool for the quantification of Ki-67, estrogen receptor (ER), and progesterone receptor (PR) in breast cancer was evaluated within a realistic study set representative of clinical routine on a total of 204 slides (72 Ki-67, 66 ER, and 66 PR slides). This represents the cohort with the largest image variance for AI tool evaluation to date, including 3 staining systems, 5 whole-slide scanners, and 1 microscope camera. These routine cases were collected without manual preselection and analyzed by 10 participant pathologists from 8 sites. Agreement rates for individual pathologists were found to be 87.6% for Ki-67 and 89.4% for ER/PR, respectively, between scoring with and without the assistance of the AI tool regarding clinical categories. Individual AI analysis results were confirmed by the majority of pathologists in 95.8% of Ki-67 cases and 93.2% of ER/PR cases. The statistical analysis provides evidence for high interobserver variance between pathologists (Krippendorff's α, 0.69) in conventional immunohistochemical quantification. Pathologist agreement increased slightly when using AI support (Krippendorff α, 0.72). Agreement rates of pathologist scores with and without AI assistance provide evidence for the reliability of immunohistochemical scoring with the support of the investigated AI tool under a large number of environmental variables that influence the quality of the diagnosed tissue images.

An app-based training for adolescents with problematic digital-media use and their parents (Res@t digital): protocol for a cluster-randomized clinical trial.

Background: Digital media-use disorders (DMUD) in adolescents are a rising phenomenon associated with psychological distress, comorbid mental disorders, and high burden on affected families. Since the ICD-11 introduced criteria for gaming disorder, these can now be transferred to describe additional DMUD associated with social media platforms and streaming services. Most evidence for effective treatments comes from cognitive-behavioral therapy (CBT). However, interventions based on theoretical models for adolescents and their parents are widely missing, leading to a significant clinical gap. Methods: Res@t digital (Resource-Strengthening Training for Adolescents with Problematic Digital-Media Use and their Parents) is the app-based translation of the first model-based digital intervention for adolescents with DMUD and their parents based on CBT. It comprises separate but content-related modules for adolescents (Res@t-A) and parents (Res@t-P), applying multimodal techniques. The effectiveness of Res@t will be evaluated within a multicenter cluster-randomized controlled evaluator-blinded pre-post follow-up trial with the waitlist control group (CG). In addition to the Res@t program in the intervention group, both groups will receive treatment as usual within primary child and adolescent psychiatric/psychotherapeutic healthcare. The primary outcome addresses DMUD symptom reduction after 10 weeks. Secondary outcomes are related to a reduction in psychological and family-related problems and an increase in parental self-efficacy. All outcomes will be assessed using standardized self-report measures. A total of 1,334 participating adolescent-parent dyads from a large clinical network throughout Germany are planned to be included in the primary analyses based on an intention-to-treat approach, applying linear mixed models. Discussion: Assuming superiority of Res@t over the control condition, the intervention has the potential to provide evidence-based treatment for a significant number of help-seeking families, supporting local healthcare structures and resources. It is a promising program for practicable implementation and flexible use in different settings. Clinical trial registration: https://drks.de, DRKS00031043.

Blinded sample size re-estimation in a comparative diagnostic accuracy study.

BACKGROUND: The sample size calculation in a confirmatory diagnostic accuracy study is performed for co-primary endpoints because sensitivity and specificity are considered simultaneously. The initial sample size calculation in an unpaired and paired diagnostic study is based on assumptions about, among others, the prevalence of the disease and, in the paired design, the proportion of discordant test results between the experimental and the comparator test. The choice of the power for the individual endpoints impacts the sample size and overall power. Uncertain assumptions about the nuisance parameters can additionally affect the sample size. METHODS: We develop an optimal sample size calculation considering co-primary endpoints to avoid an overpowered study in the unpaired and paired design. To adjust assumptions about the nuisance parameters during the study period, we introduce a blinded adaptive design for sample size re-estimation for the unpaired and the paired study design. A simulation study compares the adaptive design to the fixed design. For the paired design, the new approach is compared to an existing approach using an example study. RESULTS: Due to blinding, the adaptive design does not inflate type I error rates. The adaptive design reaches the target power and re-estimates nuisance parameters without any relevant bias. Compared to the existing approach, the proposed methods lead to a smaller sample size. CONCLUSIONS: We recommend the application of the optimal sample size calculation and a blinded adaptive design in a confirmatory diagnostic accuracy study. They compensate inefficiencies of the sample size calculation and support to reach the study aim.

Phenotyping spinal abnormalities in patients with Neurofibromatosis type 1 using whole-body MRI.

Neurofibromatosis Type 1 (NF1) has been reported to be associated with a variety of spinal abnormalities. The purpose of this study was to quantify the prevalence of spinal abnormalities in a collective of NF1 patients that is representative for the general NF1 population, to associate the co-appearance of spinal abnormalities with both NF1 and clinical symptoms and to investigate if different mutations of the NF1 gene affect the prevalence of these abnormalities. Retrospectively, 275 patients with NF1 and an age- and sex-matched collective of 262 patients were analyzed. The prevalence of spinal abnormalities was recorded. Mutational analysis of the NF1 gene was obtained in 235 NF1 patients. Associations between spinal abnormalities, clinical symptoms and genotype were investigated by binary logistic regression analysis. Prevalence of all spinal abnormalities was higher in NF1 patients than in the control group. Six characteristics of spinal abnormalities were significantly associated with NF1 (all p < 0.05). An influence of scalloping on scoliosis (OR 3.01; p = 0.002); of meningoceles (OR 7.63) and neuroforaminal tumors (OR 2.96) on scalloping, and of dural ectasia on neuroforaminal tumors (OR 1.93) was identified. Backpain and loss of motor function were associated with neuroforaminal tumors, spinal tumors and scalloping of vertebral bodies (all p < 0.05). Specific mutations of the NF1 gene were not relevantly associated with the development of spinal abnormalities. These findings can aid clinicians to improve clinical care of NF1 patients by creating awareness for co-appearences of specific spinal abnormalities and associated symptoms.

Heterogeneity of multiple sclerosis lesions in fast diffusional kurtosis imaging.

BACKGROUND: Mean kurtosis (MK), one of the parameters derived from diffusion kurtosis imaging (DKI), has shown increased sensitivity to tissue microstructure damage in several neurological disorders. METHODS: Thirty-seven patients with relapsing-remitting MS and eleven healthy controls (HC) received brain imaging on a 3T MR scanner, including a fast DKI sequence. MK and mean diffusivity (MD) were measured in the white matter of HC, normal-appearing white matter (NAWM) of MS patients, contrast-enhancing lesions (CE-L), FLAIR lesions (FLAIR-L) and black holes (BH). RESULTS: Overall 1529 lesions were analyzed, including 30 CE-L, 832 FLAIR-L and 667 BH. Highest MK values were obtained in the white matter of HC (0.814 ± 0.129), followed by NAWM (0.724 ± 0.137), CE-L (0.619 ± 0.096), FLAIR-L (0.565 ± 0.123) and BH (0.549 ± 0.12). Lowest MD values were obtained in the white matter of HC (0.747 ± 0.068 10-3mm2/sec), followed by NAWM (0.808 ± 0.163 10-3mm2/sec), CE-L (0.853 ± 0.211 10-3mm2/sec), BH (0.957 ± 0.304 10-3mm2/sec) and FLAIR-L (0.976 ± 0.35 10-3mm2/sec). While MK differed significantly between CE-L and non-enhancing lesions, MD did not. CONCLUSION: MK adds predictive value to differentiate between MS lesions and might provide further information about diffuse white matter injury and lesion microstructure.

Sample size calculation and re-estimation based on the prevalence in a single-arm confirmatory diagnostic accuracy study.

INTRODUCTION: In a confirmatory diagnostic accuracy study, sensitivity and specificity are considered as co-primary endpoints. For the sample size calculation, the prevalence of the target population must be taken into account to obtain a representative sample. In this context, a general problem arises. With a low or high prevalence, the study may be overpowered in one subpopulation. One further issue is the correct pre-specification of the true prevalence. With an incorrect assumption about the prevalence, an over- or underestimated sample size will result. METHODS: To obtain the desired power independent of the prevalence, a method for an optimal sample size calculation for the comparison of a diagnostic experimental test with a prespecified minimum sensitivity and specificity is proposed. To face the problem of an incorrectly pre-specified prevalence, a blinded one-time re-estimation design of the sample size based on the prevalence and a blinded repeated re-estimation design of the sample size based on the prevalence are evaluated by a simulation study. Both designs are compared to a fixed design and additionally among each other. RESULTS: The type I error rates of both blinded re-estimation designs are not inflated. Their empirical overall power equals the desired theoretical power and both designs offer unbiased estimates of the prevalence. The repeated re-estimation design reveals no advantages concerning the mean squared error of the re-estimated prevalence or sample size compared to the one-time re-estimation design. The appropriate size of the internal pilot study in the one-time re-estimation design is 50% of the initially calculated sample size. CONCLUSIONS: A one-time re-estimation design of the prevalence based on the optimal sample size calculation is recommended in single-arm diagnostic accuracy studies.

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.

A 12-year follow-up of a treated cocaine-dependent sample.

The study examined long-term outcomes (mortality, substance use, mental health, employment, criminal involvement) among a cocaine-dependent sample. This 12-year follow-up study, conducted in 2002-2003, updates information obtained at intake and two face-to-face interviews conducted in 1990-1991 and 1991-1992 among 321 male cocaine-dependent veterans admitted to drug treatment in 1988-1989. At the 2002-2003 follow-up, 28 had died and 266 were interviewed. A mixed model examining the longitudinal relationships demonstrated that treatment was associated with lower levels of cocaine use over the 12-year follow-up period after entry into the index treatment and more stable recovery (i.e., continuously abstinent from cocaine for at least 5 years). Few measures at intake predicted stable recovery at follow-up: only being White (vs. being African American) and having greater confidence in ability to avoid cocaine use in high-risk situations. Individuals achieving stable recovery reported less psychiatric symptoms, criminal involvement, and unemployment during the year prior to the interview. Adverse outcomes were apparent for a significant number of cocaine-dependent users who continued to use cocaine for a long period.