Unlike other prognostic tools, the EPIPHANY index is applicable across the entire spectrum of PE severity, including both incidental and symptomatic events. The model is a validation and extension of the clinical decision rule proposed in several clinical trials with the aim of pragmatically selecting low-risk patients eligible for outpatient care. These decision-making rules are based on the combination of altered vital signs (e.g., hypotension, hypoxaemia, tachycardia, etc.) and factors that point toward a high risk of bleeding or other contraindications to receiving treatment in the home. Moreover, the EPIPHANY rule incorporates another five covariates that include discriminatory characteristics typical in cancer patients that are easily accessible at patients' bedside, such as ECOG-PS, evaluation of tumour response prior to PE using RECIST 1.1 criteria, previous primary tumour resection, oxygen saturation, and the presence or absence of PE-specific symptoms.

The decision tree model classification method used after the Exhaustive CHAID procedure is one of the differences that distinguish the EPIPHANY index from other models. This design was chosen given the interest in generating a classification that would reasonably imitate authentic decision-making. This means that, unlike a binary logistic regression, which postulates the existence of additive effects that contribute to explaining outcome, decision trees factor in the existence of strong interactions between variables and are better suited to elaborating decision-making algorithms that follow the same structure. Thus, in the real world, decisions in subjects with PE are not generally made on the basis of the small additive contributions of several variables, but on the presence or absence of strong dichotomous predictors such as cardiogenic shock, acute respiratory failure, hypotension, etc. The presence of a single one of these variables indicates high risk and is fundamental in the clinical decision to intensify therapy, regardless of the contribution of the remaining covariates of a logistic regression model.

Another striking difference between the EPIPHANY index and the afore-mentioned methods is that we propose beginning to use the probability of serious complications within 15 days as the primary end point and not all-cause 30-day mortality, which had been typically used in other studies. The main argument is that the appearance of serious complications in individuals with PE treated as outpatients, far from medical supervision, can paradoxically turn low-risk patients into the most vulnerable, because of misclassification. In contrast, the probability of all-cause 30-day mortality will not necessarily affect decision-making regarding ambulatory treatment in some subgroups, as the cause of death is rarely the PE itself, and is often due to cancer progression. In fact, patients on palliative care for advanced disease are those in whom it is even more important to prevent unnecessary hospitalisation at the end of their lives. The use of the all-cause 30-day mortality end point also entails the issue of proposing intensification of PE management (e.g., with fibrinolysis) in subjects at greater risk of early mortality due to cancer, who are precisely the ones who are less likely to benefit.