An approach to trial design and analysis in the era of non-proportional hazards of the treatment effect

Background: Most randomized controlled trials with a time-to-event outcome are designed and analysed under the proportional hazards assumption, with a target hazard ratio for the treatment effect in mind. However, the hazards may be non-proportional. We address how to design a trial under such conditions, and how to analyse the results. Methods: We propose to extend the usual approach, a logrank test, to also include the Grambsch-Therneau test of proportional hazards. We test the resulting composite null hypothesis using a joint test for the hazard ratio and for time-dependent behaviour of the hazard ratio. We compute the power and sample size for the logrank test under proportional hazards, and from that we compute the power of the joint test. For the estimation of relevant quantities from the trial data, various models could be used; we advocate adopting a pre-specified flexible parametric survival model that supports time-dependent behaviour of the hazard ratio. Results: We present the mathematics for calculating the power and sample size for the joint test. We illustrate the methodology in real data from two randomized trials, one in ovarian cancer and the other in treating cellulitis. We show selected estimates and their uncertainty derived from the advocated flexible parametric model. We demonstrate in a small simulation study that when a treatment effect either increases or decreases over time, the joint test can outperform the logrank test in the presence of both patterns of non-proportional hazards. Conclusions: Those designing and analysing trials in the era of non-proportional hazards need to acknowledge that a more complex type of treatment effect is becoming more common. Our method for the design of the trial retains the tools familiar in the standard methodology based on the logrank test, and extends it to incorporate a joint test of the null hypothesis with power against non-proportional hazards. For the analysis of trial data, we propose the use of a pre-specified flexible parametric model that can represent a time-dependent hazard ratio if one is present

Investigating whether adverse prenatal and perinatal events are associated with non-clinical psychotic symptoms at age 12 years in the ALSPAC birth cohort

Background. Non-clinical psychosis-like symptoms (PLIKS) occur in about 15% of the population. It is not clear whether adverse events during early development alter the risk of developing PLIKS. We aimed to examine whether maternal infection, diabetes or pre-eclampsia during pregnancy, gestational age, perinatal cardiopulmonary resuscitation or 5-min Apgar score were associated with development of psychotic symptoms during early adolescence. Method. A longitudinal study of 6356 12-year-old adolescents who completed a semi-structured interview for psychotic symptoms in the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort. Prenatal and perinatal data were obtained from obstetric records and maternal questionnaires completed during pregnancy. Results. The presence of definite psychotic symptoms was associated with maternal infection during pregnancy [adjusted odds ratio (OR) 1.44, 95% confidence interval (CI) 1.11–1.86, p=0.006], maternal diabetes (adjusted OR 3.43, 95% CI 1.14–10.36, p=0.029), need for resuscitation (adjusted OR 1.50, 95% CI 0.97–2.31, p=0.065) and 5-min Apgar score (adjusted OR per unit decrease 1.30, 95% CI 1.12–1.50, p<0.001). None of these associations were mediated by childhood IQ score. Most associations persisted, but were less strong, when including suspected symptoms as part of the outcome. There was no association between PLIKS and gestational age or pre-eclampsia. Conclusions. Adverse events during early development may lead to an increased risk of developing PLIKS. Although the status of PLIKS in relation to clinical disorders such as schizophrenia is not clear, the similarity between these results and findings reported for schizophrenia indicates that future studies of PLIKS may help us to understand how psychotic experiences and clinical disorders develop throughout the life-course

An Examination of Student and Faculty Perceptions Regarding Music Education Transfer Student Preparedness and Experiences

Transfer students account for growing numbers in four-year music education programs. To better understand this increasing population of students, researchers employed parallel method design. One strand investigated music education faculty members’ (n = 83) perceptions of transfer student preparedness, procedures, and expectations to understand admissions processes (e.g., curricula, assessments) employed to evaluate incoming transfer students. The other strand examined music education transfer students’ (n = 12) academic, social, and personal preparedness to study music education in a comprehensive four-year music education program. The following research questions served as a guide for data collection and analysis: (a) What themes emerged for students throughout the investigation of the transfer process? (b) What are transfer students’ perceptions of academic and musical preparedness once making the transition to four-year institutions? and (c) What are college professors’ perceptions of transfer students’ academic and musical preparedness upon arrival at four-year institutions? Findings from both student and faculty perspectives suggest that transfer students exhibit three common concerns throughout the transfer process. These concerns were academic, social, and personal. Further, transfer students’ preparedness also emerged as a theme mentioned by music faculty as an obstacle for incoming students. Themes also included performance on departmental diagnostic assessments, various modes of communication among music faculty (i.e., applied, classroom), students, and university/college administrative personnel. Researchers provide an analysis and suggestions for addressing these concerns from multiple perspectives as well as suggestions for future research