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  • Adult asthma scores—development and validation of multivariable scores to identify asthma in surveys
    Publication . Sá-Sousa, Ana; Pereira, Ana Margarida; Almeida, Rute; Araújo, Luís; Couto, Mariana; Jacinto, Tiago; Freitas, Alberto; Bousquet, Jean; Fonseca, João A.
    One of the questions in epidemiology is the identification of adult asthma in studies. To develop and validate multivariable scores for adult asthma identification in epidemiological studies and to explore cutoffs to rule in/rule out asthma, compared with asthma diagnosed by a physician after clinical examination and diagnostic tests, blinded to the self-administered questions. We analyzed data (n = 711 adults) from a nationwide population-based study. The predictors were self-administered questions identified in a literature review (the Adult Asthma Epidemiological Score [A2 score]) and from the Global Allergy and Asthma Network of Excellence (GA2LEN) questionnaire (the GA2LEN Asthma Epidemiological Score [GA2LEN score]). Scores were developed using exploratory factor analysis. Internal consistency, discriminative power, and diagnostic accuracy were assessed. The A2 score comprises 8 questions (including “Did a physician confirm you had asthma?”) and the GA2LEN score comprises 6 questions (including “Have you ever had asthma?”). Both had high Cronbach α (0.89 and 0.85, respectively, for the A2 score and the GA2LEN score) and good area under the receiver-operating characteristic curve (90.4% and 89.0%). The scoring is the sum of positive answers. Asthma is present (rule in) for scores of 4 or more (specificity, 99.2%; PPV, 93.3% and 91.7%; accuracy, 89.4% and 87.4%, respectively, for the A2 score and the GA2LEN score). Asthma is excluded (rule out) for A2 scores of 0 to 1 and a GA2LEN score of 0 (sensitivity, 93.1%; NPV, 98.2% and 98.0%; accuracy 89.4% and 82.8%, respectively, for the A2 score and the GA2LEN score). These practical scores can be used to rule in/rule out asthma in epidemiological studies and clinical screening/triage settings. They may help physicians in primary care or other specialties to screen patients with asthma using a simple score with a high level of discrimination and to identify the best candidates to be referred for a diagnostic workup. Moreover, their use may contribute to reducing the inconsistencies of operational definitions of asthma across studies and surveys.
  • Multidisciplinary development and initial validation of a clinical knowledge base on chronic respiratory diseases for mHealth decision support systems
    Publication . Pereira, Ana Margarida; Jácome, Cristina; Jacinto, Tiago; Amaral, Rita; Pereira, Mariana; Sá-Sousa, Ana; Couto, Mariana; Vieira-Marques, Pedro; Martinho, Diogo; Vieira, Ana; Almeida, Ana; Martins, Constantino; Marreiros, Goreti; Freitas, Alberto; Almeida, Rute; Fonseca, João A.
    Most mobile health (mHealth) decision support systems currently available for chronic obstructive respiratory diseases (CORDs) are not supported by clinical evidence or lack clinical validation. The development of the knowledge base that will feed the clinical decision support system is a crucial step that involves the collection and systematization of clinical knowledge from relevant scientific sources and its representation in a human-understandable and computer-interpretable way. This work describes the development and initial validation of a clinical knowledge base that can be integrated into mHealth decision support systems developed for patients with CORDs. A multidisciplinary team of health care professionals with clinical experience in respiratory diseases, together with data science and IT professionals, defined a new framework that can be used in other evidence-based systems. The knowledge base development began with a thorough review of the relevant scientific sources (eg, disease guidelines) to identify the recommendations to be implemented in the decision support system based on a consensus process. Recommendations were selected according to predefined inclusion criteria: (1) applicable to individuals with CORDs or to prevent CORDs, (2) directed toward patient self-management, (3) targeting adults, and (4) within the scope of the knowledge domains and subdomains defined. Then, the selected recommendations were prioritized according to (1) a harmonized level of evidence (reconciled from different sources); (2) the scope of the source document (international was preferred); (3) the entity that issued the source document; (4) the operability of the recommendation; and (5) health care professionals’ perceptions of the relevance, potential impact, and reach of the recommendation. A total of 358 recommendations were selected. Next, the variables required to trigger those recommendations were defined (n=116) and operationalized into logical rules using Boolean logical operators (n=405). Finally, the knowledge base was implemented in an intelligent individualized coaching component and pretested with an asthma use case. Initial validation of the knowledge base was conducted internally using data from a population-based observational study of individuals with or without asthma or rhinitis. External validation of the appropriateness of the recommendations with the highest priority level was conducted independently by 4 physicians. In addition, a strategy for knowledge base updates, including an easy-to-use rules editor, was defined. Using this process, based on consensus and iterative improvement, we developed and conducted preliminary validation of a clinical knowledge base for CORDs that translates disease guidelines into personalized patient recommendations. The knowledge base can be used as part of mHealth decision support systems. This process could be replicated in other clinical areas.
  • Having concomitant asthma phenotypes is common and independently relates to poor lung function in NHANES 2007–2012
    Publication . Amaral, Rita; Fonseca, João A.; Jacinto, Tiago; Pereira, Ana M.; Malinovschi, Andrei; Janson, Christer; Alving, Kjell
    Evidence for distinct asthma phenotypes and their overlap is becoming increasingly relevant to identify personalized and targeted therapeutic strategies. In this study, we aimed to describe the overlap of five commonly reported asthma phenotypes in US adults with current asthma and assess its association with asthma outcomes. Data from the National Health and Nutrition Examination Surveys (NHANES) 2007–2012 were used (n = 30,442). Adults with current asthma were selected. Asthma phenotypes were: B-Eos-high [if blood eosinophils (B-Eos) ≥ 300/mm3]; FeNO-high (FeNO ≥ 35 ppb); B-Eos&FeNO-low (B-Eos < 150/mm3 and FeNO < 20 ppb); asthma with obesity (AwObesity) (BMI ≥ 30 kg/m2); and asthma with concurrent COPD. Data were weighted for the US population and analyses were stratified by age (< 40 and ≥ 40 years old). Of the 18,619 adults included, 1059 (5.6% [95% CI 5.1–5.9]) had current asthma. A substantial overlap was observed both in subjects aged < 40 years (44%) and ≥ 40 years (54%). The more prevalent specific overlaps in both age groups were AwObesity associated with either B-Eos-high (15 and 12%, respectively) or B-Eos&FeNO-low asthma (13 and 11%, respectively). About 14% of the current asthma patients were “non-classified”. Regardless of phenotype classification, having concomitant phenotypes was significantly associated with (adjusted OR, 95% CI) ≥ 2 controller medications (2.03, 1.16–3.57), and FEV1 < LLN (3.21, 1.74–5.94), adjusted for confounding variables. A prevalent overlap of commonly reported asthma phenotypes was observed among asthma patients from the general population, with implications for objective asthma outcomes. A broader approach may be required to better characterize asthma patients and prevent poor asthma outcomes.
  • InspirerMundi—remote monitoring of inhaled medication adherence through objective verification based on combined image processing techniques
    Publication . Pedro, Vieira-Marques; Rute, Almeida; Teixeira, João F.; Valente, José; Jácome, Cristina; Cachim, Afonso; Guedes, Rui; Pereira, Ana; Jacinto, Tiago; Fonseca, João A.
    The adherence to inhaled controller medications is of critical importance for achieving good clinical results in patients with chronic respiratory diseases. Self-management strategies can result in improved health outcomes and reduce unscheduled care and improve disease control. However, adherence assessment suffers from difficulties on attaining a high grade of trustworthiness given that patient self-reports of high-adherence rates are known to be unreliable. Objective Aiming to increase patient adherence to medication and allow for remote monitoring by health professionals, a mobile gamified application was developed where a therapeutic plan provides insight for creating a patient-oriented self-management system. To allow a reliable adherence measurement, the application includes a novel approach for objective verification of inhaler usage based on real-time video capture of the inhaler's dosage counters. This approach uses template matching image processing techniques, an off-the-shelf machine learning framework, and was developed to be reusable within other applications. The proposed approach was validated by 24 participants with a set of 12 inhalers models. Results Performed tests resulted in the correct value identification for the dosage counter in 79% of the registration events with all inhalers and over 90% for the three most widely used inhalers in Portugal. These results show the potential of exploring mobile-embedded capabilities for acquiring additional evidence regarding inhaler adherence. This system helps to bridge the gap between the patient and the health professional. By empowering the first with a tool for disease self-management and medication adherence and providing the later with additional relevant data, it paves the way to a better-informed disease management decision.
  • The influence of individual characteristics and non-respiratory diseases on blood eosinophil count
    Publication . Amaral, Rita; Jacinto, Tiago; Malinovschi, Andrei; Janson, Christer; Price, David; Fonseca, João A.; Alving, Kjell
    Blood eosinophil (B-Eos) count is an emerging biomarker in the management of respiratory disease but determinants of B-Eos count besides respiratory disease are poorly described. Therefore, we aimed to evaluate the influence of non-respiratory diseases on B-Eos count, in comparison to the effect on two other biomarkers: fraction of exhaled nitric oxide (FeNO) and C-reactive protein (CRP), and to identify individual characteristics associated with B-Eos count in healthy controls.
  • Disentangling the heterogeneity of allergic respiratory diseases by latent class analysis reveals novel phenotypes
    Publication . Amaral, Rita; Bousquet, Jean; Pereira, Ana M.; Araújo, Luís M.; Sá‐Sousa, Ana; Jacinto, Tiago; Almeida, Rute; Delgado, Luís; Fonseca, João A.
    Background Refined phenotyping of allergic diseases may unravel novel phenotypes. Conjunctivitis as an independent disorder has never been approached. Aim To identify distinct classes of allergic respiratory diseases using latent class analysis (LCA) and distinguish each class using classification and regression tree (CART) analysis. Methods Seven hundred and twenty‐eight adults from the Portuguese general population study ICAR had a structured medical interview combined with blood collection, skin prick tests, spirometry with bronchodilation, and exhaled nitric oxide. LCA was applied to 19 variables. The CART algorithm selected the most likely variables distinguishing LCA‐classes. Results A six‐class model was obtained. Class 1 (25%): nonallergic participants without bronchial or ocular symptoms. Classes 2 (22%) and 3 (11%): nasal and ocular (low levels) symptoms without nasal impairment, monosensitized (Class 2) or polysensitized (Class 3). Class 4 (13%): polysensitized participants with high levels of nasal and ocular symptoms, and nasal impairment. Classes 5 (16%) and 6 (14%): high level of nasal, bronchial and ocular symptoms with nasal impairment (non‐allergic or polysensitized, respectively). Participants in classes 5 and 6 had more bronchial exacerbations and unscheduled medical visits (P < 0.001). Ocular symptoms were significantly higher in classes with nasal impairment, compared to those without impairment (P < 0.001) or no nasal symptom (P < 0.001). CART highlighted ocular symptoms as the most relevant variable in distinguishing LCA‐classes. Conclusion Novel severe phenotypes of participants with co‐occurrence of ocular, nasal and bronchial symptoms, and exacerbation‐prone were identified. The tree algorithm showed the importance of the ocular symptoms in the expression of allergic diseases phenotypes.
  • A systematic review of asthma phenotypes derived by data-driven methods
    Publication . Cunha, Francisco; Amaral, Rita; Jacinto, Tiago; Sousa-Pinto, Bernardo; Fonseca, João A.
    Classification of asthma phenotypes has a potentially relevant impact on the clinical management of the disease. Methods for statistical classification without a priori assumptions (data-driven approaches) may contribute to developing a better comprehension of trait heterogeneity in disease phenotyping. This study aimed to summarize and characterize asthma phenotypes derived by data-driven methods. We performed a systematic review using three scientific databases, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. We included studies reporting adult asthma phenotypes derived by data-driven methods using easily accessible variables in clinical practice. Two independent reviewers assessed studies. The methodological quality of included primary studies was assessed using the ROBINS-I tool. We retrieved 7446 results and included 68 studies of which 65% (n = 44) used data from specialized centers and 53% (n = 36) evaluated the consistency of phenotypes. The most frequent data-driven method was hierarchical cluster analysis (n = 19). Three major asthma-related domains of easily measurable clinical variables used for phenotyping were identified: personal (n = 49), functional (n = 48) and clinical (n = 47). The identified asthma phenotypes varied according to the sample's characteristics, variables included in the model, and data availability. Overall, the most frequent phenotypes were related to atopy, gender, and severe disease. This review shows a large variability of asthma phenotypes derived from data-driven methods. Further research should include more population-based samples and assess longitudinal consistency of data-driven phenotypes.
  • Comparison of hypothesis- and data-driven asthma phenotypes in NHANES 2007–2012: the importance of comprehensive data availability
    Publication . Amaral, Rita; Pereira, Ana M.; Jacinto, Tiago; Malinovschi, Andrei; Janson, Christer; Alving, Kjell; Fonseca, João A.
    Half of the adults with current asthma among the US National Health and Nutrition Examination Survey (NHANES) participants could be classified in more than one hypothesis-driven phenotype. A data-driven approach applied to the same subjects may allow a more useful classification compared to the hypothesis-driven one. To compare previously defined hypothesis-driven with newly derived data-driven asthma phenotypes, identified by latent class analysis (LCA), in adults with current asthma from NHANES 2007–2012. Adults (≥ 18 years) with current asthma from the NHANES were included (n = 1059). LCA included variables commonly used to subdivide asthma. LCA models were derived independently according to age groups: < 40 and ≥ 40 years old. Two data-driven phenotypes were identified among adults with current asthma, for both age groups. The proportions of the hypothesis-driven phenotypes were similar among the two data-driven phenotypes (p > 0.05). Class A < 40 years (n = 285; 75%) and Class A ≥ 40 years (n = 462; 73%), respectively, were characterized by a predominance of highly symptomatic asthma subjects with poor lung function, compared to Class B < 40 years (n = 94; 25%) and Class B ≥ 40 years (n = 170; 27%). Inflammatory biomarkers, smoking status, presence of obesity and hay fever did not markedly differ between the phenotypes. Both data- and hypothesis-driven approaches using clinical and physiological variables commonly used to characterize asthma are suboptimal to identify asthma phenotypes among adults from the general population. Further studies based on more comprehensive disease features are required to identify asthma phenotypes in population-based studies.
  • Real-time clinical decision support at the point of care
    Publication . Pereira, Ana Margarida; Jácome, Cristina; Amaral, Rita; Jacinto, Tiago; Fonseca, João A.
    This chapter starts by introducing the complex process of shared clinical decision-making, the value of incorporating patient-reported outcome measures into clinical decisions and the increasing usefulness of clinical decision support systems to enhance the quality and safety of healthcare. It then gives examples of three tools for clinical decision support at the point of care, which were designed to support health professionals and patients in the assessment, treatment and long-term management of chronic respiratory diseases.
  • Correlation between rhinomanometry and spirometry parameters in 971 adults
    Publication . Gonçalves, Ivânia; Jacinto, Tiago; Amaral, Rita; Pereira, Ana M.; Araújo, Luís M.; Couto, Mariana; Fonseca, João A.; Amaral, Rita
    There is a lack of published studies about the association between  rhinomanometry and spirometry results. Some studies have shown a moderate correlation between spirometry parameters and other nasal objective measures such as Peak Nasal Inspiratory Flow (PNIF). We aimed to study the correlation between rhinomanometry and spirometry parameters.