The BOUNCE research took place in 4 European international locations (Finland, Italy, Israel and Portugal) aiming to assess psychosocial resilience of BC people through the 1st 18 months submit-diagnosis as a operate of psychological (trait and ongoing), sociodemographic, lifetime-type, and medical variables (disorder and treatment method-similar) (H2020 EU undertaking BOUNCE GA no. 777167 for far more details see https://www.bounce-task.eu/). The study enrolled 706 ladies among March 2018 and December 2019 in accordance to the adhering to conditions: (i) Inclusion: age 40–70 years, histologically confirmed BC stage I, II, or III, operation as component of the treatment, some form of systemic remedy for BC (ii) Exclusion: Record or lively extreme psychiatric condition (Big depression, bipolar ailment, psychosis), distant metastases, historical past or remedy of other malignancy within last 5 years, other significant concomitant illnesses diagnosed inside the past 12 months, big surgical procedure for a critical sickness or trauma in just 4 weeks prior to research entry, or absence of total recovery from the effects of surgical procedure, being pregnant or breast feeding. The BOUNCE examine is a longitudinal, observational examine involving seven measurement waves: Baseline (taking put 2–5 weeks after surgical procedure or biopsy and viewed as as Month [M0], and subsequently at three-month intervals (M3, M6, M9, M12, M15, M12) with a remaining comply with up measurement at M18. Details on every single of the key final result variables had been gathered at all time details. Info from the remaining time points served secondary investigation targets of the over-all job.
The whole BOUNCE study was accepted by the moral committee of the European Institute of Oncology (Approval No R868/18—IEO 916) and the ethical committees of every single participating scientific center. All contributors have been informed in detail relating to the intention and procedural particulars of the analyze and delivered created consent. All methods were being carried out in accordance with suitable tips and restrictions.
For the present analyses we viewed as sociodemographic, lifetime-design and style, health care variables and self-reported psychological qualities registered at the time of BC diagnosis and, also, at the very first stick to up assessment, carried out 3 months just after prognosis. The selection to pool predictor details from the first three months publish diagnosis was guided by the next considerations: (a) Emotional responses and recognition of emotional and behavioral adaptive procedures are typically not entirely created right until the whole scope of the illness can be appreciated by the affected person, (b) This period defines a realistically limited observation window to report resilience predictors in schedule clinical follow, nonetheless not too long in check out of the just one-year study finish-issue, (c) past scientific tests have revealed that significant modifications in psychological effectively-staying usually consider area later in the trajectory of health issues.
Self-reported psychological overall health status at 12 months submit-analysis, indexed by the full score on the 14-item Medical center Stress and Melancholy Scale (HADS)16, served as the end result variable in the present analyses (see Supplementary Information and facts). The clinically validated cutoff score of 16/42 factors in a huge range of languages was employed to determine sufferers who noted probably clinically considerable signs at M0 and at M1217,18. Subsequently, individuals were being assigned to two classes: (a) people who noted non-clinically substantial signs and symptoms of stress and anxiety and melancholy at M0 (i.e., right away subsequent BC diagnosis) and clinically major symptomatology at M12 (i.e., 1 calendar year post prognosis) according to validated cutoffs on HADS total score (Deteriorated Mental Wellbeing group), and (b) all those who noted mild symptomatology all over the first 12 months publish analysis (Secure-Superior Mental Well being group). Thus, the Deteriorated Psychological Overall health team comprised persons who scored < 16 points at M0 and ≥ 16 points at M12, whereas the Stable-Good Mental Health group comprised persons who scored < 16 points at M0, M3, M6, M9 and M12 assessment time points.
The analysis pipeline adopted to address the main and secondary objective of the study entailed preprocessing steps, feature selection, model training and testing19. Model 1 was designed to optimize prediction of one-year adverse mental health outcomes by considering all available variables collected at M0 and M3, including HADS Anxiety, HADS Depression, and Global QoL. Model 2 was designed to obtain personalized risk profiles and focus on potential modifiable factors (by omitting HADS Anxiety, HADS Depression, and Global QoL measured at M0 and M3). Feature selection, using a Random Forest algorithm, was incorporated into the ML-based pipeline alongside the classification algorithm to select only the relevant features for training and testing the final model (see Supplementary Information). The area under the Receiver Operating Characteristic curve (ROC AUC) was used to evaluate the performance of the cross-validated model on the test set by estimating the following metrics: specificity, sensitivity, accuracy, precision, F-measure, and AUC.
Data preprocessing and handling of missing data
Initially, raw data were rescaled to zero mean and unit variance and ordinal variables were recoded into dummy binary variables. Cases and variables with more than 90% of missingness were excluded from the final dataset. Remaining missing values were replaced by the global median value (supplementary analyses showed that applying multivariate imputation had negligible effect on model performance see Supplementary Material).
Feature selection was conducted using a meta-transformer built on a Random Forest (RF) algorithm20 which assigns weights to the features and ranks them according to their relative importance. The maximum number of features to be selected by the estimator was set to the default value (i.e. the square root of the total number of features) in order to identify all important variables that contribute to the risk prediction of mental health deterioration. The feature selection scheme was incorporated into the ML-based pipeline alongside the classification algorithm to select only the relevant features for training and testing the final model.
Model training and validation
To address the rather common problem of model overfitting in machine learning applications in clinical research we adopted a cross-validation scheme with holdout data for the final model evaluation. Model overfitting occurs because a model that has less training error (i.e. misclassifications on training data) can have poor generalization (expected classification errors on new unseen data) than a model with higher training error. As a result, we took extra steps to avoid partially overlapping subsets of cases by splitting our dataset into training and testing subsets with a validation set. Hence, model testing was always performed on unseen cases which were not considered during the training phase and, consequently, did not influence the feature selection process. This procedure helps to minimize misclassifications on the training phase while also ensuring lessening of generalization errors.
In the present study, a fivefold data split for hyper-parameters (i.e. cross-validation with grid search) was applied on the training, testing and validation subsets, to prevent overfitting and maximize model generalizability performance on the test set. A grid search procedure with an inner fivefold cross-validation was applied on the validation set for hyper-parameters tuning and model selection. To this end, the best parameters from a grid of parameter values on the trained models were selected enabling the optimization of the classification results on the test set.
Classification with balanced random forest algorithm
Class imbalance handling was addressed using random under-sampling methods to balance the subsets combined inside an ensemble. Specifically, a balanced random forest classifier from the imbalanced-learn MIT-licensed library21 was applied to deal with the classification of imbalanced classes within our dataset. Balanced Random Forest22 combines the down sampling majority class technique and the ensemble learning approach, artificially adjusting the class distribution so that classes are represented equally in each tree in the forest. In this manner, each bootstrap sample contains balanced down-sampled data. Applying random-under sampling to balance the different bootstraps in an RF classifier could have classification performance superior to most of the existing conventional ML-based estimators while alleviating the problem of learning from imbalanced datasets.
The following metrics to assess the performance of the learning algorithm applied on imbalanced data: specificity (true negative rate) sensitivity (true positive rate) accuracy, precision, and F-measure. These metrics are functions of the confusion matrix given the (correct) target values and the estimated targets as returned by the classifier during the testing phase. We also used the Receiver Operating Characteristic (ROC) curve to represent the tradeoff between the false negative and false positive rates for every possible cut off. The Area Under the Curve (AUC) was also computed according to the estimated ROC analysis.
Personalized risk profiles (model 2 only)
Following the analysis steps described in the preceding paragraphs, model-agnostic analysis was implemented on the set of variables that emerged as significant features from Model 2 to identify predictor variables of primary importance for a particular mental health prediction23,24. This analysis supports the interpretability of the set of variables that emerged as significant features toward patient classifications. Specifically, model agnostic analysis can be applied: (i) at the global (variable-specific) level to help clarify how each feature contributes toward model decisions per patient group and, (ii) at the local (i.e., patient-specific) level to identify predictor variables of primary importance for a particular mental health prediction. In view of the lack of precedence in the literature we selected mathematical models that made no assumptions about data structure. The break-down plots (local level) were developed using the dalex Python package19,23 with the default values in the arguments of the main function were applied.