57 Risk factors: a systematic review 2 be associated with longer sleep duration.56 However, this finding remains to be replicated. In general, the quality of the included studies on the influence of genetic variation on steroid-induced APRs and sleep problems is very low (Supplemental Tables 5 and 6). Most patient cohorts were very small which could explain the inability to demonstrate significant differences between genetic profiles. Other limitations include the lack of adjustments for multiple testing and confounding variables, as well as the absence of a replication cohort. This makes it impossible to provide evidence based recommendations regarding genetic susceptibility. Larger studies with proper replication are warranted. Study limitations Some strengths and limitations should be discussed. For our systematic review, we used six different search engines and did not limit our search on our predefined risk factors (PICO’s). This generated an extensive and complete search result and cross reference check did not reveal any new evidence. Furthermore, two high quality tools (QUIPS and GRADE) were used. Both tools complementarily facilitate a structured assessment and interpretation of results. All evidence screening, data extraction and assessment was performed by two independent researchers, limiting inter-individual differences. A limitation includes that the interpretability of the results of this review is overall of very low quality of evidence, partly due to the average high risk of bias within single studies. This indicates that more extensive research designed to primarily investigate steroid-induced APRs and sleep is warranted. We included a screen of 245 papers that reported on outcomes of clinical pediatric ALL trials. Of these 245, only six mentioned either APRs or sleep problems as a steroid-induced toxicity, of which one was included in our review.42 Numerous large trial papers which included (randomization for) steroids did not report APRs or sleep problems as adverse events, even though other toxicities such as osteonecrosis or infections were prospectively collected.76-78 These trials are mainly designed to improve (event free) survival, and/or to a lesser extent to decrease treatment induced toxicity. APRs and sleep problems are common (steroid-induced) toxicities, which can influence HRQoL substantially. An integrated system to measure and report both toxicities should be implemented in upcoming treatment protocols. Integration of patient-reported outcome measures (PROMs) could be valuable to establish a systematic approach.79,80 Clinical implications and conclusions Based on this systematic review of literature, we conclude that there is no high level of evidence for risk factors for developing steroid-induced APR or sleep problems in children with ALL. There are few high quality prospective studies and patient numbers are small. Methods of measurement are heterogeneous and evidence is weak. However, current evidence suggests that type and dose of steroids are not related to APRs, but may be related
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