Ariel O Mace's research while affiliated with Telethon Kids Institute and other places

Introduction Group A streptococcus (GAS) infections, such as pharyngitis and impetigo, can lead to rheumatic fever and rheumatic heart disease (RHD). Australian Aboriginal and Torres Strait Islander populations experience high rates of RHD and GAS skin infection, yet rates of GAS pharyngitis are unclear. Anecdotally, clinical presentations of pharyngitis, including tonsillar hypertrophy and sore throat, are uncommon. This study aimed to develop a standardised set of tonsil photographs and determine tonsil size distribution from an urban paediatric population. Methods A prospective cohort of children aged 3–15 years were recruited at the public events “Discover Day” and “Telethon Weekend” (October 2017) in Perth, Western Australia, Australia. Tonsil photographs, symptomatology, and GAS rapid antigen detection tests (RADT) were collected. Tonsil size was graded from the photographs using the Brodsky Grading Scale of tonsillar hypertrophy (Brodsky) by two independent clinicians, and inter-rater reliability calculated. Pharyngitis symptoms and GAS RADT were correlated, and immediate results provided. Results Four hundred and twenty-six healthy children participated in the study over three days. The median age was seven years [interquartile range (IQR) 5.9–9.7 years]. Tonsil photographs were collected for 92% of participants, of which 62% were rated as good-quality photographs and 79% were deemed of adequate quality for assessment by both clinicians. When scored by two independent clinicians, 57% received the same grade. Average Brodsky grades (between clinicians) were 11%, 35%, 28%, 22% and 5% of grades 0,1,2,3 and 4, respectively. There was moderate agreement in grading using photographs, and minimal to weak agreement for signs of infection. Of 394 participants, 8% reported a sore throat. Of 334 GAS RADT performed, <1% were positive. Discussion We report the first standardised use of paediatric tonsil photographs to assess tonsil size in urban-living Australian children. This provides a proof of concept from an urban-living cohort that could be compared with children in other settings with high risk of GAS pharyngitis or rheumatic fever such as remote-living Australian Indigenous populations.

We compared the epidemiology, severity and management of hospitalized respiratory syncytial virus (n = 305) and human metapneumovirus (n = 39) bronchiolitis in a setting with high respiratory virus testing (95% of admissions tested). Respiratory syncytial virus-positive infants were younger and tended to require more hydration support and longer hospital stays compared to human metapneumovirus-positive infants. Respiratory support requirements were similar between groups despite significant age differences.

Objectives: Despite evidence supporting earlier discharge of well-appearing febrile infants at low risk of serious bacterial infection (SBI), admissions for ≥48 hours remain common. Prospective safety monitoring may support broader guideline implementation. Methods: A sequential Bayesian safety monitoring framework was used to evaluate a new hospital guideline recommending early discharge of low-risk infants. Hospital readmissions within 7 days of discharge were regularly assessed against safety thresholds, derived from historic rates and expert opinion, and specified a priori (8 per 100 infants). Infants aged under 3 months admitted to 2 Western Australian metropolitan hospitals for management of fever without source were enrolled (August 2019-December 2021), to a prespecified maximum 500 enrolments. Results: Readmission rates remained below the prespecified threshold at all scheduled analyses. Median corrected age was 34 days, and 14% met low-risk criteria (n = 71). SBI was diagnosed in 159 infants (32%), including urinary tract infection (n = 140) and bacteraemia (n = 18). Discharge occurred before 48 hours for 192 infants (38%), including 52% deemed low-risk. At study completion, 1 of 37 low-risk infants discharged before 48 hours had been readmitted (3%), for issues unrelated to SBI diagnosis. In total, 20 readmissions were identified (4 per 100 infants; 95% credible interval 3, 6), with >0.99 posterior probability of being below the prespecified noninferiority threshold, indicating acceptable safety. Conclusions: A Bayesian monitoring approach supported safe early discharge for many infants, without increased risk of readmission. This framework may be used to embed safety evaluations within future guideline implementation programs to further reduce low-value care.

Background: COVID-19 is a new multi-organ disease causing considerable worldwide morbidity and mortality. While many recognized pathophysiological mechanisms are involved, their exact causal relationships remain opaque. Better understanding is needed for predicting their progression, targeting therapeutic approaches, and improving patient outcomes. While many mathematical causal models describe COVID-19 epidemiology, none have described its pathophysiology. Methods: In early 2020, we began developing such causal models. The SARS-CoV-2 virus's rapid and extensive spread made this particularly difficult: no large patient datasets were publicly available; the medical literature was flooded with sometimes conflicting pre-review reports; and clinicians in many countries had little time for academic consultations. We used Bayesian network (BN) models, which provide powerful calculation tools and directed acyclic graphs (DAGs) as comprehensible causal maps. Hence, they can incorporate both expert opinion and numerical data, and produce explainable, updatable results. To obtain the DAGs, we used extensive expert elicitation (exploiting Australia's exceptionally low COVID-19 burden) in structured online sessions. Groups of clinical and other specialists were enlisted to filter, interpret and discuss the literature and develop a current consensus. We encouraged inclusion of theoretically salient latent (unobservable) variables, likely mechanisms by extrapolation from other diseases, and documented supporting literature while noting controversies. Our method was iterative and incremental: systematically refining and validating the group output using one-on-one follow-up meetings with original and new experts. 35 experts contributed 126 hours face-to-face, and could review our products. Results: We present two key models, for the initial infection of the respiratory tract and the possible progression to complications, as causal DAGs and BNs with corresponding verbal descriptions, dictionaries and sources. These are the first published causal models of COVID-19 pathophysiology. Conclusions: Our method demonstrates an improved procedure for developing BNs via expert elicitation, which other teams can implement to model emergent complex phenomena. Our results have three anticipated applications: (i) freely disseminating updatable expert knowledge; (ii) guiding design and analysis of observational and clinical studies; (iii) developing and validating automated tools for causal reasoning and decision support. We are developing such tools for the initial diagnosis, resource management, and prognosis of COVID-19, parameterized using the ISARIC and LEOSS databases.

Background: Pneumonia remains a leading cause of hospitalization and death among young children worldwide, and the diagnostic challenge of differentiating bacterial from non-bacterial pneumonia is the main driver of antibiotic use for treating pneumonia in children. Causal Bayesian networks (BNs) serve as powerful tools for this problem as they provide clear maps of probabilistic relationships between variables and produce results in an explainable way by incorporating both domain expert knowledge and numerical data. Methods: We used domain expert knowledge and data in combination and iteratively, to construct, parameterise and validate a causal BN to predict causative pathogens for childhood pneumonia. Expert knowledge elicitation occurred through a series of group workshops, surveys and one-on-one meetings involving 6-8 experts from diverse domain areas. The model performance was evaluated based on both quantitative metrics and qualitative expert validation. Sensitivity analyses were conducted to investigate how the target output is influenced by varying key assumptions of particular high degree of uncertainty around data or domain expert knowledge. Results: Designed to apply to a cohort of children with X-ray confirmed pneumonia who presented to a tertiary paediatric hospital in Australia, the resulting BN offers explainable and quantitative predictions on a range of variables of interest, including the diagnosis of bacterial pneumonia, detection of respiratory pathogens in the nasopharynx, and the clinical phenotype of a pneumonia episode. Satisfactory numeric performance has been achieved including an area under the receiver-operating characteristics curve of 0.8 in predicting clinically-confirmed bacterial pneumonia with sensitivity 88% and specificity 66% given certain input scenarios (i.e., information that is available and entered into the model) and trade-off preferences (i.e., relative weightings of the consequences of false positive versus false negative predictions). We specifically highlight that a desirable model output threshold for practical use is very dependent upon different input scenarios and trade-off preferences. Three commonly encountered scenarios were presented to demonstrate the potential usefulness of the BN outputs in various clinical pictures. Conclusions: To our knowledge, this is the first causal model developed to help determine the causative pathogen for paediatric pneumonia. We have shown how the method works and how it would help decision making on the use of antibiotics, providing insight into how computational model predictions may be translated to actionable decisions in practice. We discussed key next steps including external validation, adaptation and implementation. Our model framework and the methodological approach can be adapted beyond our context to broad respiratory infections and geographical and healthcare settings.

Background Diagnosing urinary tract infections (UTIs) in children in the emergency department (ED) is challenging due to the variable clinical presentations and difficulties in obtaining a urine sample free from contamination. Clinicians need to weigh a range of observations to make timely diagnostic and management decisions, a difficult task to achieve without support due to the complex interactions among relevant factors. Directed acyclic graphs (DAG) and causal Bayesian networks (BN) offer a way to explicitly outline the underlying disease, contamination and diagnostic processes, and to further make quantitative inference on the event of interest thus serving as a tool for decision support. Methods We prospectively collected data on children present to ED with suspected UTIs. Through knowledge elicitation workshops and one-on-one meetings, a DAG was co-developed with clinical domain experts (the Expert DAG) to describe the causal relationships among variables relevant to paediatric UTIs. The Expert DAG was combined with prospective data and further domain knowledge to inform the development of an application-oriented BN (the Applied BN), designed to support the diagnosis of UTI. We assessed the performance of the Applied BN using quantitative and qualitative methods. Results We summarised patient background, clinical and laboratory characteristics of 431 episodes of suspected UTIs enrolled from May 2019 to November 2020. The Expert DAG was presented with a narrative description, elucidating how infection, specimen contamination and management pathways causally interact to form the complex picture of paediatric UTIs. Parameterised using prospective data and expert-elicited parameters, the Applied BN achieved an excellent and stable performance in predicting Escherichia coli culture results, with a mean area under the receiver operating characteristic curve of 0.86 and a mean log loss of 0.48 based on 10-fold cross-validation. The BN predictions were reviewed via a validation workshop, and we illustrate how they can be presented for decision support using three hypothetical clinical scenarios. Conclusion Causal BNs created from both expert knowledge and data can integrate case-specific information to provide individual decision support during the diagnosis of paediatric UTIs in ED. The model aids the interpretation of culture results and the diagnosis of UTIs, promising the prospect of improved patient care and judicious use of antibiotics.

Background Pneumonia remains a leading cause of hospitalization and death among young children worldwide, and the diagnostic challenge of differentiating bacterial from non-bacterial pneumonia is the main driver of antibiotic use for treating pneumonia in children. Causal Bayesian networks (BNs) serve as powerful tools for this problem as they provide clear maps of probabilistic relationships between variables and produce results in an explainable way by incoporating both domain expert knowledge and numerical data. Methods We used domain expert knowledge and data in combination and iteratively, to construct, parameterise and validate a causal BN to predict causative pathogens for childhood pneumonia. Expert knowledge elicitation occurred through a series of group workshops, surveys and one-on-one meetings involving 6-8 experts from diverse domain areas. The model performance was evaluated based on both quantitative metrics (area under the receiver-operator curve (AUROC) and log loss) and qualitative expert validation. Sensitivity analyses were conducted to investigate how the target output is influenced by varying key assumptions of particular high degree of uncertainty around data or domain expert knowledge. Results Designed to apply to a cohort of children with X-ray confirmed pneumonia who presented to a tertiary paediatric hospital in Australia, the resulting BN offers explainable and quantitative predictions on a range of variables of interest, including the diagnosis of bacterial pneumonia, detection of respiratory pathogens in the nasopharynx, and the clinical phenotype of a pneumonia episode. Satisfactory numeric performance has been achieved including an AUROC of 0.8 in predicting the clinical diagnosis of bacterial pneumonia. Three commonly encountered scenarios were presented to demonstrate the potential usefulness of the BN outputs in various clinical pictures. Conclusions To our knowledge, this is the first causal model developed to help determine the causative pathogen for paediatric pneumonia. It can be utilized to derive recommendations to support more directed and judicious use of antimicrobials for relevant cohorts. The BN needs further validation before it can be clinically implemented. Our model framework and the methodological approach can be adapted beyond our context to broad respiratory infections and geographical and healthcare settings.

Background Diagnosing urinary tract infections (UTIs) in children in the emergency department (ED) is challenging due to the variable clinical presentations and difficulties in obtaining a urine sample free from contamination. Clinicians need to weigh a range of observations to make timely diagnostic and management decisions, a difficult task to achieve without support due to the complex interactions among relevant factors. Directed acyclic graphs (DAG) and causal Bayesian networks (BN) offer a way to explicitly outline the underlying disease, contamination and diagnostic processes, and to further make quantitative inference on the event of interest thus serving as a tool for decision support. Methods We prospectively collected data on children present to ED with suspected UTIs. Through knowledge elicitation workshops and one-on-one meetings, a DAG was co-developed with domain experts (the Expert DAG) to describe the causal relationships among variables relevant to paediatric UTIs. The Expert DAG was combined with prospective data and further domain knowledge to inform the development of an application-oriented BN (the Applied BN), designed to support the diagnosis of UTI. We assessed the performance of the Applied BN using quantitative and qualitative methods. Results We summarised patient background, clinical and laboratory characteristics of 431 episodes of suspected UTIs enrolled from May 2019 to November 2020. The Expert DAG was presented with a narrative description, elucidating how infection, specimen contamination and management pathways causally interact to form the complex picture of paediatric UTIs. Parameterised using prospective data and expert-elicited parameters, the Applied BN achieved an excellent and stable performance in predicting E.coli culture results, with a mean AUROC of 0.86 and a mean log loss of 0.48 based on 10-fold cross-validation. The BN predictions were reviewed via a validation workshop, and we illustrate how they can be presented for decision support using three hypothetical clinical scenarios. Conclusion Causal BNs created from both expert knowledge and data can integrate case-specific information to provide individual decision support during the diagnosis of paediatric UTIs in ED. The model aids the interpretation of culture results and the diagnosis of UTIs, promising the prospect of improved patient care and judicious use of antibiotics.

Background COVID-19 is a new multi-organ disease, caused by the SARS-CoV-2 virus, resulting in considerable worldwide morbidity and mortality. While many recognized pathophysiological mechanisms are involved, their exact causal relationships remain opaque. A better understanding is needed for predicting their progression, targeting therapeutic approaches, and improving patient outcomes. While many mathematical causal models describe COVID-19 epidemiology, none have been developed for its pathophysiology. The virus’s rapid and extensive spread and therapeutic responses made this particularly difficult. Initially, no large patient datasets were publicly available, and their data remains limited. The medical literature was flooded with unfiltered, technical and sometimes conflicting pre-review reports. Clinicians in many countries had little time for academic consultations, and in-person meetings were unsafe. Methods and Findings In early 2020, we began a major project to develop causal models of the pathophysiological processes underlying the disease’s clinical manifestations. We used Bayesian network (BN) models, because they provide both powerful tools for calculation and clear maps of probabilistic causal influence between semantically meaningful variables, as directed acyclic graphs (DAGs). Hence, they can incorporate expert opinion and numerical data, and produce explainable results. Dynamic causal BNs, which represent successive “time slices” of the system, can capture feedback loops and long-term disease progression. To obtain the likely causal structures, we used extensive elicitation of expert opinion in structured online sessions. Centered in Australia, with its exceptionally low COVID-19 burden, we managed to obtain many consultation hours. Groups of clinical and other subject matter specialists, all independent volunteers, were enlisted to filter, interpret and discuss the literature and develop a current consensus. We aimed to capture the experts’ understanding, so we encouraged discussion and inclusion of theoretically salient latent (i.e., unobservable) variables, documented supporting literature while noting controversies, and allowed experts to propose mechanisms by extrapolation from other diseases. Intermediary experts with some combined expertise facilitated the exchange of knowledge to BN modelers and vice versa. Our method was iterative and incremental: we systematically refined and checked the group output with one-on-one follow-up meetings with the original and new experts to validate previous results. In total, 35 experts contributed 126 face-to-face hours, and could review our products. Conclusions Our method demonstrates and describes an improved procedure for developing BNs via expert elicitation, which can be implemented rapidly by other teams modeling emergent complex phenomena. The results presented are two key models, for the initial infection of the respiratory tract and the possible progression to complications, as causal DAGs and BNs with corresponding verbal descriptions, dictionaries and sources. These are the first published causal models of COVID-19 pathophysiology, with three anticipated applications: (i) making expert knowledge freely available in a readily understandable and updatable form; (ii) guiding design and analysis of observational and clinical studies, by identifying potential mediators, confounders, and modifiers of treatment effects; (iii) developing and validating parameterized automated tools for causal reasoning and decision support, in clinical and policy settings. We are currently developing such tools for the initial diagnosis, resource management, and prognosis of COVID-19, parameterized using the ISARIC and LEOSS databases.