49 Risk factors: a systematic review 2 Medical history With our search, we did not identify any studies describing medical history as a risk factor for steroid-induced sleeping problems. Genetic predisposition Only one study (n = 72) investigated genetic variation as possible risk factor for steroidinduced sleep problems in ALL.56 Vallance et al. studied 99 polymorphic loci in candidate genes associated with glucocorticoid metabolism. They included actigraphy data of 72 Caucasian patients, no replication cohort was used. They did not adjust for multiple testing and did not describe controlling for confounding variables (Supplemental Table 6). Three different SNPs in two genes were described in relation to dexamethasone induced sleeping problems. A homozygous variant in the α2-Heremans-Schmid glycoprotein (AHSG) gene was associated with longer sleep time and longer sleep duration during dexamethasone treatment.56 Carriership of two SNPs in the Interleukin-6 (IL-6) gene was not significantly associated with sleep problems during dexamethasone treatment (Supplemental Table 6).56 Other factors We identified two additional studied risk factors for sleep problems. Dexamethasone pharmacokinetics was investigated in two ALL studies. One study (n = 24) did not find an association of higher dexamethasone levels (trough levels following four days of dexamethasone) with sleep problems.53 Another study (n = 100) described that a decrease of the cumulative time above a threshold of 100 nM dexamethasone was associated with increased actual sleep time. Furthermore, in a univariate analysis wake after sleep onset (WASO) increased and sleep efficiency and sleep time decreased as the dexamethasone area under the curve increased. However, multivariate analysis did not reveal statistical evidence independent of the dexamethasone area under the curve level.56 The same group studied albumin levels and the occurrence of sleep problems and did not find a significant relation between both.56
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