Abstract
BackgroundHereditary transthyretin amyloidosis (ATTRv amyloidosis) is an inherited disease, where the study of family history holds importance. This study evaluates the changes of age-of-onset (AOO) and other age-related clinical factors within and among families affected by ATTRv amyloidosis.MethodsWe analysed information from 934 trees, focusing on family, parents, probands and siblings relationships. We focused on 1494 female and 1712 male symptomatic ATTRV30M patients. Results are presented alongside a comparison of current with historical records. Clinical and genealogical indicators identify major changes.ResultsOverall, analysis of familial data shows the existence of families with both early and late patients (1/6). It identifies long familial follow-up times since patient families tend to be diagnosed over several years. Finally, results show a large difference between parent-child and proband-patient relationships (20-30 years).ConclusionsThis study reveals that there has been a shift in patient profile, with a recent increase in male elderly cases, especially regarding probands. It shows that symptomatic patients exhibit less variability towards siblings, when compared to other family members, namely the transmitting ancestors' age of onset. This can influence genetic counselling guidelines.

Abstract
Transthyretin-associated Familial Amyloid Polyneuropathy (TTR-FAP) is a chronic fatal disease with a high incidence in Portugal. It is therefore relevant to provide professionals and citizens with a tool that enables a detailed geographical and territorial study. For this reason, we have developed an web based application that brings together techniques applied to spatial data that allow the study of the historical progression and growth of cases in patients' residential areas and areas of origin as well as an epidemic forecast. The tool enables the exploration of geographical longitudinal data at national, district and county levels. High density regions and periods can be visually identified according to parameters selected by the user. The visual evaluation of the data and its comparison across different time spans of the disease era can have an impact on more informed decision making by those working with patients to improve their quality of life, treatment or follow-up. The tool is available online for data exploration and its code is available on GitHub for adaptation to other geospatial scenarios.

Abstract
IntroductionHereditary transthyretin amyloidosis (ATTRv amyloidosis) is a rare neurological hereditary disease clinically characterized as severe, progressive, and life-threatening while the age of onset represents the moment in time when the first symptoms are felt. In this study, we present and discuss our results on the study, development, and evaluation of an approach that allows for time-to-event prediction of the age of onset, while focusing on genealogical feature construction. Materials and methodsThis research was triggered by the need to answer the medical problem of when will an asymptomatic ATTRv patient show symptoms of the disease. To do so, we defined and studied the impact of 77 features (ranging from demographic and genealogical to familial disease history) we studied and compared a pool of prediction algorithms, namely, linear regression (LR), elastic net (EN), lasso (LA), ridge (RI), support vector machines (SV), decision tree (DT), random forest (RF), and XGboost (XG), both in a classification as well as a regression setting; we assembled a baseline (BL) which corresponds to the current medical knowledge of the disease; we studied the problem of predicting the age of onset of ATTRv patients; we assessed the viability of predicting age of onset on short term horizons, with a classification framing, on localized sets of patients (currently symptomatic and asymptomatic carriers, with and without genealogical information); and we compared the results with an out-of-bag evaluation set and assembled in a different time-frame than the original data in order to account for data leakage. ResultsCurrently, we observe that our approach outperforms the BL model, which follows a set of clinical heuristics and represents current medical practice. Overall, our results show the supremacy of SV and XG for both the prediction tasks although impacted by data characteristics, namely, the existence of missing values, complex data, and small-sized available inputs. DiscussionWith this study, we defined a predictive model approach capable to be well-understood by medical professionals, compared with the current practice, namely, the baseline approach (BL), and successfully showed the improvement achieved to the current medical knowledge.

Abstract
Transthyretin (TTR)-related familial amyloid polyneuropathy (ATTRv) is a life-threatening autosomal dominant disease and the age of onset represents the moment when first symptoms are felt. Accurately predicting the age of onset for a given patient is relevant for risk assessment and treatment management. In this work, we evaluate the impact of combining prediction models obtained from neighboring time windows on prediction error. We propose Symmetric (Sym) and Asymmetric (Asym) models which represent two different averaging approaches. These are incorporated with a weighting mechanism as to create Symmetric (Sym), Symmetric-weighted (Sym-w), Asymmetric (Asym), and Asymmetric-weighted (Asym-w). These four ensemble models are then compared to the original approach which is focused on individual regression base learners namely: Baseline (BL), Decision Tree (DT), Elastic Net (EN), Lasso (LA), Linear Regression (LR), Random Forest (RF), Ridge (RI), Support Vector Regressor (SV) and XGBoost (XG). Our results show that by aggregating predictions from neighbor models the average mean absolute error obtained by each base learner decreases. Overall, the best results are achieved by regression-based ensemble tree models as base learners.

Abstract
Transthyretin Familial Amyloid Polyneuropathy (TTR-FAP) is a neurological genetic illness that inflicts severe symptoms after the onset occurs. Age of onset represents the moment a patient starts to experience the symptoms of a disease. An accurate prediction of this event can improve clinical and operational guidelines that define the work of doctors, nurses, and operational staff. In this work, we transform family trees into compact vectors, that is, embeddings, and handle these as input features to predict the age of onset of patients with TTR-FAP. Our purpose is to evaluate how information present in genealogical trees can be transformed and used to improve a regression-based setting for TTR-FAP age of onset prediction. Our results show that by combining manual and graph-embeddings features there is a decrease in the mean prediction error when there is less information regarding a patient's family. With this work, we open the way for future work in representation learning for genealogical data, enabling a more effective exploitation of machine learning approaches.