Adaptive Survival Trials

Mid-study design modifications are becoming increasingly accepted in confirmatory clinical trials, so long as appropriate methods are applied such that error rates are controlled. It is therefore unfortunate that the important case of time-to-event endpoints is not easily handled by the standard theory. We analyze current methods that allow design modifications to be based on the full interim data, i.e., not only the observed event times but also secondary endpoint and safety data from patients who are yet to have an event. We show that the final test statistic may ignore a substantial subset of the observed event times. Since it is the data corresponding to the earliest recruited patients that is ignored, this neglect becomes egregious when there is specific interest in learning about long-term survival. An alternative test incorporating all event times is proposed, where a conservative assumption is made in order to guarantee type I error control. We examine the properties of our proposed approach using the example of a clinical trial comparing two cancer therapies.Comment: 22 pages, 7 figure

Health related quality of life and psychopathological distress in risk taking and self-harming adolescents with full-syndrome, subthreshold and without borderline personality disorder: rethinking the clinical cut-off?

Background: Diagnostic standards do not acknowledge developmental specifics and differences in the clinical presentation of adolescents with borderline personality disorder (BPD). BPD is associated with severe impairments in health related quality of life (HRQoL) and increased psychopathological distress. Previously no study addressed differences in HRQoL and psychopathology in adolescents with subthreshold and full-syndrome BPD as well as adolescents at-risk for the development but no current BPD. Methods: Drawing on data from a consecutive sample of N = 264 adolescents (12–17 years) presenting with risk-taking and self-harming behavior at a specialized outpatient clinic, we investigated differences in HRQoL (KIDSCREEN-52) and psychopathological distress (SCL-90-R) comparing adolescents with no BPD (less than 3 criteria fulfilled), to those with subthreshold (3–4 BPD criteria) and full-syndrome BPD (5 or more BPD criteria). Group differences were analyzed using one-way analysis of variance with Sidak corrected contrasts or Chi-Square test for categorical variables. Results: Adolescents with subthreshold and full-syndrome BPD presented one year later at our clinic and were more likely female. Adolescents with subthreshold and full-syndrome BPD showed greater Axis-I and Axis-II comorbidity compared to adolescents with no BPD, and reported greater risk-taking behaviour, self-injury and suicidality. Compared to those without BPD, adolescents with subthreshold and full-syndrome BPD reported significantly reduced HRQoL. Adolescents with sub-threshold BPD and those with full-syndrome BPD did not differ on any HRQoL dimension, with the exception of Self-Perception. Similar, groups with sub-threshold and full-syndrome BPD showed no significant differences on any dimension of self-reported psychopathological distress, with the exception of Hostility. Conclusions: Findings highlight that subthreshold BPD in adolescents is associated with impairments in HRQoL and psychopathological distress comparable to full-syndrome BPD. Findings raise awareness on the importance of early detection and question the diagnostic validity and clinical utility of existing cut-offs. Findings support a lower diagnostic cut-off for adolescent BPD, to identify those at-risk at an early stage

Sample size reassessment and hypothesis testing in adaptive survival trials

Mid-study design modifications are becoming increasingly accepted in confirmatory clinical trials, so long as appropriate methods are applied such that error rates are controlled. It is therefore unfortunate that the important case of time-to-event endpoints is not easily handled by the standard theory. We analyze current methods that allow design modifications to be based on the full interim data, i.e., not only the observed event times but also secondary endpoint and safety data from patients who are yet to have an event. We show that the final test statistic may ignore a substantial subset of the observed event times. An alternative test incorporating all event times is found, where a conservative assumption must be made in order to guarantee type I error control. We examine the power of this approach using the example of a clinical trial comparing two cancer therapies

Psychosocial functioning in adolescents with non-suicidal self-injury: the roles of childhood maltreatment, borderline personality disorder and depression

Background: There is a lack of studies examining psychosocial functioning in patients with non-suicidal self-injury (NSSI), especially in adolescents, and rates of impaired functioning in existing literature vary considerably. These variations may be attributable to further risk factors that influence psychosocial functioning. Thus, the aim of the study was to examine whether adolescent NSSI patients with childhood maltreatment (CM), a known risk factor for lower psychosocial functioning, may differ from adolescent NSSI patients without CM, and whether these differences may be explained by the severity of comorbid disorders. Specifically, we examined whether severity of borderline personality disorder (BPD), depression and posttraumatic stress disorder may explain differences in psychosocial functioning in NSSI patients with and without CM. Methods: Data of 368 adolescents with NSSI disorder from an outpatient clinic were analyzed using structural equation modeling. Clinicans' rating of the Global Assessment of Functioning Scale (GAF) was collected, in addition to clinical interviews. Results: Results indicate that GAF scores were lower among NSSI patients with CM and that the difference in psychosocial functioning between these groups was explained by BPD and depression severity. Conclusions: Psychosocial functioning in NSSI patients varies depending on whether they have experienced CM or not. Specifically, these differences seem to be attributable to higher BPD and depression severity in adolescent NSSI patients with CM. Clinicians should ensure to assess CM and focus on BPD and depression severity in this population. Treatment of BPD and depression may notably reduce psychosocial impairment in NSSI patients with CM

Adolescent borderline personality traits and dyadic behavior shape mother-adolescent cortisol synchrony.

BACKGROUND Associations between parent and child cortisol levels ("cortisol synchrony") are often reported and positive synchrony may mark dyadic regulation on a physiological level. Although dyadic behavior during interaction and adolescent borderline personality disorder (BPD) traits are linked with individual and dyadic regulatory capacities, little is known about how both factors influence parent-adolescent cortisol synchrony. We hypothesized that cortisol synchrony would differ depending on behavioral synchrony, i.e., smooth reciprocal dyadic interaction patterns, adolescent BPD traits, and their interactions. METHODS Multilevel state-trait modeling was implemented to investigate associations between concurrent mother-adolescent state cortisol and mother-adolescent average cortisol levels in a community sample of 76 mother-adolescent dyads. Three saliva samples were collected across interaction paradigms. Behavioral synchrony was observed, and adolescent BPD traits were evaluated using clinical interviews. RESULTS First, behavioral synchrony and absence of BPD traits were linked with positive associations between adolescent and maternal state cortisol (positive synchrony), BPD traits with negative associations (negative synchrony). When interaction effects were examined, results were more nuanced. In low-risk dyads (higher behavioral synchrony, no BPD traits) asynchrony was found. When risk (BPD traits) and resource (higher behavioral synchrony) were combined, synchrony was positive. Lastly, in high-risk dyads (lower behavioral synchrony, adolescent BPD traits), negative synchrony was observed. Average adolescent and maternal cortisol levels were consistently positively associated in dyads with higher risk. CONCLUSIONS Positive dyadic interaction patterns are associated with positive state cortisol synchrony in mother-adolescent dyads and could buffer the effect of BPD traits, possibly supporting the process of physiological regulation

Lauenen. Reformierte Pfarrkirche. Ergebnisse der Bauforschungen von 1983/84

Restaurierungsarbeiten an der Kirche von Lauenen veranlassten, in verschiedenen Etappen zwischen Sommer 1983 und Januar 1984 archäologische und baugeschichtliche Untersuchungen durchzuführen. Die Publikation umfasst die Ergebnisse zu den Funden und Befunden der Vorgängerkirche aus dem 16. Jh. und deren Veränderungen seit der Reformation. Es fügen sich die Auswertung der Münzen und ihrer Bedeutung für die Datierung sowie die Resultate der anthropologischen Untersuchungen an den Skeletten an

On the accuracy of ERS-1 orbit predictions

Since the launch of ERS-1, the D-PAF (German Processing and Archiving Facility) provides regularly orbit predictions for the worldwide SLR (Satellite Laser Ranging) tracking network. The weekly distributed orbital elements are so called tuned IRV's and tuned SAO-elements. The tuning procedure, designed to improve the accuracy of the recovery of the orbit at the stations, is discussed based on numerical results. This shows that tuning of elements is essential for ERS-1 with the currently applied tracking procedures. The orbital elements are updated by daily distributed time bias functions. The generation of the time bias function is explained. Problems and numerical results are presented. The time bias function increases the prediction accuracy considerably. Finally, the quality assessment of ERS-1 orbit predictions is described. The accuracy is compiled for about 250 days since launch. The average accuracy lies in the range of 50-100 ms and has considerably improved

Self-rated risk as a predictor of suicide attempts among high-risk adolescents

Background: Predicting suicide attempts is a challenging task for clinicians and researchers, particularly among high-risk individuals (i.e. adolescents with lifetime suicide attempts). In this study, we examined whether adolescents were able to predict their own risk of attempting suicide in the future and whether borderline personality disorder (BPD) or depressive symptoms impacted the predictive value of self-ratings. Methods: Structured clinical assessments were conducted at baseline and after 12 months in a high-risk sample of treatment-seeking adolescents (n = 134; 12-17y.; 90% female) with at least one lifetime suicide attempt. Results: During the follow-up period, n = 51 participants (38%) attempted suicide at least once. Self-rated risk was a significant predictor for the recurrence of a suicide attempt, whereas BPD and depression were not. While there was no significant interaction between self-rated risk and BPD, a negative interaction emerged between self-rated risk and depression in the prediction of a suicide attempt. Greater depression severity diminished the predictive value of self-ratings. Limitations: Depression severity was measured using a questionnaire, not a clinical interview. The findings may not be applicable to less burdened samples. Conclusions: Asking high-risk adolescents to rate their own risk of attempting suicide appears to be an easy to apply method in improving the prediction of future suicide attempts in the clinical context