Code availabilityAll code for data cleaning and analysis associated with the current submission is available upon request to the corresponding author and is provided as part of the replication package.

Frontotemporal dementia (FTD), marked by impairments in behavior, language and sometimes motor function, is a common form of early-onset dementia 1 . Approximately 20-30% of FTD is caused by autosomal dominant mutations (familial, or f-FTD), usually in one of three genes: chromosome 9 open reading frame 72 (C9orf72), progranulin (GRN) or microtubule-associated protein tau (MAPT) 2 . FTD is uniformly fatal, and there are no approved therapies; however, a growing number of new treatments targeting C9orf72, GRN and MAPT are moving into clinical trials 3,4 . Experience from Alzheimer's disease (AD), spinal muscular Temporal order of clinical and biomarker changes in familial frontotemporal dementia

Background Design and analysis of clinical trials for rare and ultra-rare disease pose unique challenges to the practitioners. Meeting conventional power requirements is infeasible for diseases where sample sizes are inherently very small. Moreover, rare disease populations are generally heterogeneous and widely dispersed, which complicates study enrollment and design. Leveraging all available information in rare and ultra-rare disease trials can improve both drug development and informed decision-making processes. Main text Bayesian statistics provides a formal framework for combining all relevant information at all stages of the clinical trial, including trial design, execution, and analysis. This manuscript provides an overview of different Bayesian methods applicable to clinical trials in rare disease. We present real or hypothetical case studies that address the key needs of rare disease drug development highlighting several specific Bayesian examples of clinical trials. Advantages and hurdles of these approaches are discussed in detail. In addition, we emphasize the practical and regulatory aspects in the context of real-life applications. Conclusion The use of innovative trial designs such as master protocols and complex adaptive designs in conjunction with a Bayesian approach may help to reduce sample size, select the correct treatment and population, and accurately and reliably assess the treatment effect in the rare disease setting.

Background Our objective was to assess the association between intensive care unit (ICU)‐free days and patient outcomes in pediatric prehospital care and to evaluate whether ICU‐free days is a more sensitive outcome measure for emergency medical services research in this population. Methods This study used data from a previous pediatric prehospital trial. The original study enrolled patients ≤12 years of age and compared bag‐valve‐mask‐ventilation (BVM) versus endotracheal intubation (ETI) during prehospital resuscitation. For the current study, we defined ICU‐free days as 30 minus the number of days in the ICU (range, 0–30 days) and assigned 0 ICU‐free days for death within 30 days. We compared ICU‐free days between the original study treatment groups (BVM vs ETI) and with the original trial outcomes of survival to hospital discharge and Pediatric Cerebral Performance Category (PCPC). Results Median ICU‐free days for the BVM group (n = 404) versus ETI group (n = 416) was not statistically different: 0 ICU‐free days (interquartile range, 0–10) versus 0 (0–0), P = 0.219. Median ICU‐free days were greater for BVM group in 3 subgroups: foreign body aspiration 30 (0–30) versus 0 (0–21), P = 0.028; child maltreatment 0 (0–14.2) versus 0 (0‐0), P = 0.004; and respiratory arrest 25 (1–29) versus 7.5 (0–27.7), P = 0.015. In the original trial, neither survival nor PCPC demonstrated differences in all 3 subgroups—survival was greater with BVM for child maltreatment and respiratory arrest and favorable PCPC was greater with BVM for foreign body aspiration. Overall, in the current study, patients with more ICU‐free days also had greater survival to hospital discharge and more favorable PCPC scores. Conclusions This initial study of the association between ICU‐free days and patient outcomes during prehospital pediatric resuscitation appears to support the use of ICU‐free days as a clinical endpoint in this population. ICU‐free days may be more sensitive than either mortality or PCPC alone while capturing aspects of both measures.

Introduction While the Dominantly Inherited Alzheimer Network Trials Unit (DIAN‐TU) was ongoing, external data suggested higher doses were needed to achieve targeted effects; therefore, doses of gantenerumab were increased 5‐fold, and solanezumab was increased 4‐fold. We evaluated to what extent mid‐trial dose increases produced a dose‐dependent treatment effect. Methods Using generalized linear mixed effects (LME) models, we estimated the annual low‐ and high‐dose treatment effects in clinical, cognitive, and biomarker outcomes. Results Both gantenerumab and solanezumab demonstrated dose‐dependent treatment effects (significant for gantenerumab, non‐significant for solanezumab) in their respective target amyloid biomarkers (Pittsburgh compound B positron emission tomography standardized uptake value ratio and cerebrospinal fluid amyloid beta 42), with gantenerumab demonstrating additional treatment effects in some downstream biomarkers. No dose‐dependent treatment effects were observed in clinical or cognitive outcomes. Conclusions Mid‐trial dose escalation can be implemented as a remedy for an insufficient initial dose and can be more cost effective and less burdensome to participants than starting a new trial with higher doses, especially in rare diseases. Highlights We evaluated the dose‐dependent treatment effect of two different amyloid‐specific immunotherapies. Dose‐dependent treatment effects were observed in some biomarkers. No dose‐dependent treatment effects were observed in clinical/cognitive outcomes, potentially due to the fact that the modified study may not have been powered to detect such treatment effects in symptomatic subjects at a mild stage of disease exposed to high (or maximal) doses of medication for prolonged durations.