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S.F. Fustolo-Gunnink et al.
rect for all possible confounders. In short, the association between IUGR and bleeding is complex, our model only indicates that it is a good predictor for bleeding, but we cannot draw any causal conclusion based on this informa- tion. This applies to all individual covariates in the model.
Various possible limitations of our study need to be dis- cussed. Firstly, we could not externally validate our model because a similar database is currently not available. Secondly, identification of prognostic variables could pos- sibly have been improved with a prior systematic review assessing all potential predictors. However, despite this limitation, our model contains variables generally consid- ered best candidates for predicting major bleeding, as many of them were included in various existing baseline models. Some variables, such as mean platelet volume and immature platelet count, could not be included in our model because they were not routinely measured. Thirdly, the time a major bleed occurs is not similar to the time it is diagnosed on an ultrasound scan, because major intracranial bleeds in neonates are often asymptomatic, and detected during routine screening. To address this issue, we performed two additional sensitivity analyses, one in which we corrected time of bleeding based on whether or not minor bleeding was visible on prior ultra- sound scans, and one in which we removed events for which we could not determine whether they occurred prior to or after the bleeding. Results of these analyses
Figure 3. Dynamic, cross-validat- ed c-index. This graph represents the dynamic, cross-validated c- index of the main model. A c-index of 1 resembles a model that dis- criminates perfectly between patients with and without major bleeding, while a c-index of 0.5 indicates that the prediction is as good as chance. For each time- point, the number at risk at the beginning of that day has been reported, as well as the total num- ber of major bleeds that occurred during those 24 hours. For exam- ple, at the start of day 1, the num- ber of patients still at risk was 604, and during this day 22 neonates developed a major bleed.
Figure 4. Change in probability of having a major bleed within 3 days for two example patients. Day 0 is the day of onset of severe thrombocytopenia (T0). Characteristics of child A: gesta- tional age (weeks+days) 27+2, birthweight 1100 grams, 2 days old at T0, sepsis, mechanical ventilation, two platelet transfu- sions, platelet counts (x109/L): 41, 104, 47, and 88. Bilateral grade III intraventricular hemorrhage on day 2. Characteristics of child B: gestational age (weeks+days) 32+3, birth weight 1175 grams, 5 days old at T0, sepsis, no mechanical ventila- tion, no platelet transfusions, platelet counts (x109/L) 4, 53, 49, 63, 195 and 376. No major bleed. Days 3-7 not shown because no substantial change in bleeding risk occurred. During study days 1-3, the predicted risk of major bleeding within the subsequent 3 days is substantially higher in child A than in child B, indicating that the use of this prediction model during that time-period would have correctly identified child A as being at a high risk of bleeding.
showed only minor changes in hazard ratios of individual coefficients, suggesting that this problem does not sub- stantially affect the predictive power of our model (Online Supplementary Table S3). Fourthly, after day 6, the c-index drops below 0.60, possibly due to a lower event rate, therefore the model should be applied with caution after day 6. We hypothesize that the variation in predictive accuracy over time, depicted in Figure 2, may be caused by a balance between having enough clinical information to predict (difficult on days 1 and 2), and enough events to fit a good model (difficult after day 4). Fifthly, the risk of bleeding in neonates in our population may have been affected by treatment with platelet transfusions. Therefore, the risks calculated using our model may be an underestimation of the ‘true’ risk (without transfusion). However, there are no cohorts available in which platelet transfusions were not administered and various studies, including the previously described randomized controlled trial, suggest that the effect of platelet transfusions on bleeding risk may be limited.6,22–24 We therefore estimate that our model’s predictions are accurate. Finally, four neonates had a gestational age at birth of less than 24 weeks. In addition, local policies differed with respect to active support for neonates born at a gestational age between 24+0 and 25+6 weeks. Therefore, the neonates with a gestational age less than 26 weeks in our popula- tion might be a selection of neonates for whom good out-
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haematologica | 2019; 104(11)