Abstract
Experimental assessment of different missing data imputation methods often compute error rates between the original values and the estimated ones. This experimental setup relies on complete datasets that are injected with missing values. The injection process is straightforward for the Missing Completely At Random and Missing At Random mechanisms; however, the Missing Not At Random mechanism poses a major challenge, since the available artificial generation strategies are limited. Furthermore, the studies focused on this latter mechanism tend to disregard a comprehensive baseline of state-of-the-art imputation methods. In this work, both challenges are addressed: four new Missing Not At Random generation strategies are introduced and a benchmark study is conducted to compare six imputation methods in an experimental setup that covers 10 datasets and five missingness levels (10% to 80%). The overall findings are that, for most missing rates and datasets, the best imputation method to deal with Missing Not At Random values is the Multiple Imputation by Chained Equations, whereas for higher missingness rates autoencoders show promising results.

Abstract
Background: Most previous studies assessing multimorbidity in asthma assessed the frequency of individual comorbid diseases. Objective: We aimed to assess the frequency and clinical and economic impact of co-occurring groups of comorbidities (comorbidity patterns using the Charlson Comorbidity Index) on asthma hospitalizations. Methods: We assessed the dataset containing a registration of all Portuguese hospitalizations between 2011-2015. We applied three different approaches (regression models, association rule mining, and decision trees) to assess both the frequency and impact of comorbidities patterns in the length-of-stay, in-hospital mortality and hospital charges. For each approach, separate analyses were performed for episodes with asthma as main and as secondary diagnosis. Separate analyses were performed by participants' age group. Results: We assessed 198340 hospitalizations in patients >18 years old. Both in hospitalizations with asthma as main or secondary diagnosis, combinations of diseases involving cancer, metastasis, cerebrovascular disease, hemiplegia/paraplegia, and liver disease displayed a relevant clinical and economic burden. In hospitalizations having asthma as a secondary diagnosis, we identified several comorbidity patterns involving asthma and associated with increased length-of-stay (average impact of 1.3 [95%CI=0.6-2.0]-3.2 [95%CI=1.8-4.6] additional days), in-hospital mortality (OR range=1.4 [95%CI=1.0-2.0]-7.9 [95%CI=2.6-23.5]) and hospital charges (average additional charges of 351.0 [95%CI=219.1-482.8] to 1470.8 [95%CI=1004.6-1937.0]) Euro compared with hospitalizations without any registered Charlson comorbidity). Consistent results were observed with association rules mining and decision tree approaches. Conclusions: Our findings highlight the importance not only of a complete assessment of patients with asthma, but also of considering the presence of asthma in patients admitted by other diseases, as it may have a relevant impact on clinical and health services outcomes.

Abstract
Background: Approximately 62% of patients with breast cancer with a pathogenic variant (BRCA1 or BRCA2) undergo primary breast-conserving therapy. Objective: The study aims to develop a personalized risk management decision support tool for carriers of a pathogenic variant (BRCA1 or BRCA2) who underwent breast-conserving therapy for unilateral early-stage breast cancer. Methods: We developed a Bayesian network model of a hypothetical cohort of carriers of BRCA1 or BRCA2 diagnosed with stage I/II unilateral breast cancer and treated with breast-conserving treatment who underwent subsequent second primary cancer risk-reducing strategies. Using event dependencies structured according to expert knowledge and conditional probabilities obtained from published evidence, we predicted the 40-year overall survival rate of different risk-reducing strategies for 144 cohorts of women defined by the type of pathogenic variants (BRCA1 or BRCA2), age at primary breast cancer diagnosis, breast cancer subtype, stage of primary breast cancer, and presence or absence of adjuvant chemotherapy. Results: Absence of adjuvant chemotherapy was the most powerful factor that was linked to a dramatic decline in survival. There was a negligible decline in the mortality in patients with triple-negative breast cancer, who received no chemotherapy and underwent any secondary risk-reducing strategy, compared with surveillance. The potential survival benefit from any risk-reducing strategy was more modest in patients with triple-negative breast cancer who received chemotherapy compared with patients with luminal breast cancer. However, most patients with triple-negative breast cancer in stage I benefited from bilateral risk-reducing mastectomy and risk-reducing salpingo-oophorectomy or just risk-reducing salpingo-oophorectomy. Most patients with luminal stage I/II unilateral breast cancer benefited from bilateral risk-reducing mastectomy and risk-reducing salpingo-oophorectomy. The impact of risk-reducing salpingo-oophorectomy in patients with luminal breast cancer in stage I/II increased with age. Most older patients with the BRCA1 and BRCA2 pathogenic variants in exons 12-24/25 with luminal breast cancer may gain a similar survival benefit from other risk-reducing strategies or surveillance. Conclusions: Our study showed that it is mandatory to consider the complex interplay between the types of BRCA1 and BRCA2 pathogenic variants, age at primary breast cancer diagnosis, breast cancer subtype and stage, and received systemic treatment. As no prospective study results are available at the moment, our simulation model, which will integrate a decision support system in the near future, could facilitate the conversation between the health care provider and patient and help to weigh all the options for risk-reducing strategies leading to a more balanced decision.

Abstract
PurposeTo develop, implement and assess the results of psychoeducation to improve the QoL of parents with CHD newborns.MethodsParticipants were parents of inpatient newborns with the diagnosis of non-syndromic CHD. We conducted a parallel RCT with an allocation ratio of 1:1 (intervention vs. control), considering the newborns, using mixed methods research. The intervention group received psychoeducation (Parental Psychoeducation in CHD [PPeCHD]) and the usual routines, and the control group received just the regular practices. The allocation concealment was assured. PI was involved in enrolling participants, developing and implementing the intervention, data collection and data analysis. We followed the Consolidated Standards of Reporting Trials (CONSORT) guidelines.ResultsParents of eight newborns were allocated to the intervention group (n = 15 parents) and eight to the control group (n = 13 parents). It was performed as an intention-to-treat (ITT) analysis. In M2 (4 weeks), the intervention group presented better QoL levels in the physical, psychological, and environmental domains of World Health Organization Quality of Life instrument (WHOQOL-Bref). In M3 (16 weeks), scores in physical and psychological domains maintained a statistically significant difference between the groups.ConclusionsThe PPeCHD, the psychoeducational intervention we developed, positively impacted parental QoL. These results support the initial hypothesis. This study is a fundamental milestone in this research field, adding new essential information to the literature.

Abstract
Several studies demonstrate that the structure of the brain increases in hierarchical complexity throughout development. We tested if the structure of artificial neural networks also increases in hierarchical complexity while learning a developing task, called the balance beam problem. Previous simulations of this developmental task do not reflect a necessary premise underlying development: a more complex structure can be built out of less complex ones, while ensuring that the more complex structure does not replace the less complex one. In order to address this necessity, we segregated the input set by subsets of increasing Orders of Hierarchical Complexity. This is a complexity measure that has been extensively shown to underlie the complexity behavior and hypothesized to underlie the complexity of the neural structure of the brain. After segregating the input set, minimal neural network models were trained separately for each input subset, and adjacent complexity models were analyzed sequentially to observe whether there was a structural progression. Results show that three different network structural progressions were found, performing with similar accuracy, pointing towards self-organization. Also, more complex structures could be built out of less complex ones without substituting them, successfully addressing catastrophic forgetting and leveraging performance of previous models in the literature. Furthermore, the model structures trained on the two highest complexity subsets performed better than simulations of the balance beam present in the literature. As a major contribution, this work was successful in addressing hierarchical complexity structural growth in neural networks, and is the first that segregates inputs by Order of Hierarchical Complexity. Since this measure can be applied to all domains of data, the present method can be applied to future simulations, systematizing the simulation of developmental and evolutionary structural growth in neural networks.

Abstract