149 Migraine attack incidence in relation to ovulation 7 fit, over-dispersion was examined using the deviance-to-degrees of freedom ratio, which had a value of 0.68, indicating no over-dispersion. The model was conditioned on individual participants as fixed effects, with each participant serving as their own control, to account for within-subject variability and control for individual differences. Our primary outcome was the onset of migraine attacks. We considered any missing diary entries as no migraine. If a patient missed one diary entry between two migraine days, we classified it as a migraine day, as it represented a single attack. All statistical analyses were performed in RStudio, version 4.4.0. For the mixed model, R package lme4 was used. For the case crossover model the survival package was used, and for the SCCS model the calculations were done with the base R stats package. P values < 0·05 were deemed statistically significant. Subgroup and validation analyses Subgroup analyses were performed for the WHAT-hormone subgroup using the same three models as previously mentioned, but the day of a positive LH-surge test was used to determine ovulation. An additional subgroup analysis was performed for participants that fulfilled ICHD-3 criteria of menstrual migraine, i.e., who had migraine attacks occurring in the perimenstrual window in at least two out of three consecutive cycles.19 A diagnosis of menstrual migraine could not be determined in a small subset of women followed for fewer than three menstrual cycles. A complete case analysis was performed with the mixed model and including all participants with chronic migraine that were excluded from the primary analyses. Additionally, we calculated the mean difference between the calculated ovulation date and the true ovulation date in the WHAT-hormone subgroup for validation purposes. Ethical approval Ethical approval for the anonymized use of headache e-diaries was obtained from the Medical Ethical committee of the Leiden University Medical Centre (LUMC). Participants did not have to provide additional informed consent. Patients in the LHC database that actively declared that they did not want to participate in medical research were not screened for eligibility. For the WHAT-hormone subgroup in which ovulation tests were performed, additional ethical approval was obtained by the Medical Ethical committee of the LUMC (NL74161.058.20). All these participants provided written informed consent.
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