Publications

BLEMUR, or Bluetooth Low Energy Model of User Risk, is a model of the probability of alert at a given duration and distance of an index case for a specific configuration of settings for an Exposure Notification (EN) system.The Google-Apple EN framework operates in the duration and Bluetooth Low Energy (BLE) signal attenuation domains. However, many public health definitions of "exposure" to a disease are based upon the distance between an index case and another person. To bridge the conceptual gap for public health authorities (PHAs) from the familiar distance-and-duration space to the signal attenuation-and-duration space, BLEMUR uses BLE signal attenuation as a proxy for distance between people, albeit an imprecise one. This paper will discuss the EN settings that can be manipulated, the BLE data collected, how data support a model of the relationship between measured attenuation and distance between phones, and how BLEMUR calculates the probability of alert for a distance and duration based on the settings and data.

Automated Exposure Notication (AEN) was implemented in 2020 to supplement traditional contact tracing for COVID-19 by estimating "too close for too long" proximities of people using the service. AEN uses Bluetooth messages to privately label and recall proximity events, so that persons who were likely exposed to SARS-CoV-2 can take the appropriate steps recommended by their health care authority. This paper describes an agent-based model that estimates the effects of AEN deployment on COVID-19 caseloads and public health workloads in the context of other critical public health measures available during the COVID-19 pandemic. We selected simulation variables pertinent to AEN deployment options, varied them in accord with the system dynamics available in 2020-2021, and calculated the outcomes of key metrics across repeated runs of the stochastic multi-week simulation. SimAEN's parameters were set to ranges of observed values in consultation with public health professionals and the rapidly accumulating literature on COVID-19 transmission; the model was validated against available population-level disease metrics. Estimates from SimAEN can help public health officials determine what AEN deployment decisions (e.g., configuration, workflow integration, and targeted adoption levels) can be most effective in their jurisdiction, in combination with other COVID-19 interventions (e.g., mask use, vaccination, quarantine and isolation periods).

There is mounting evidence linking the cumulative effects of repetitive head impacts to neuro-degenerative conditions. Robust clinical assessment tools to identify mild traumatic brain injuries are needed to assist with timely diagnosis for return-to-field decisions and appropriately guide rehabilitation. The focus of the present study is to investigate the potential for oculomotor features to complement existing diagnostic tools, such as measurements of Optic Nerve Sheath Diameter (ONSD) and Immediate Post-concussion Assessment and Cognitive Testing (ImPACT). Thirty-one high school American football and soccer athletes were tracked through the course of a sports season. Given the high risk of repetitive head impacts associated with both soccer and football, our hypotheses were that (1) ONSD and ImPACT scores would worsen through the season and (2) oculomotor features would effectively capture both neurophysiological changes reflected by ONSD and neuro-functional status assessed via ImPACT. Oculomotor features were used as input to Linear Mixed-Effects Regression models to predict ONSD and ImPACT scores as outcomes. Prediction accuracy was evaluated to identify explicit relationships between eye movements, ONSD, and ImPACT scores. Significant Pearson correlations were observed between predicted and actual outcomes for ONSD (Raw = 0.70; Normalized = 0.45) and for ImPACT (Raw = 0.86; Normalized = 0.71), demonstrating the capability of oculomotor features to capture neurological changes detected by both ONSD and ImPACT. The most predictive features were found to relate to motor control and visual-motor processing. In future work, oculomotor models, linking neural structures to oculomotor function, can be built to gain extended mechanistic insights into neurophysiological changes observed through seasons of participation in contact sports.

Diagnosis of COVID-19 at point of care is vital to the containment of the global pandemic. Point of care ultrasound (POCUS) provides rapid imagery of lungs to detect COVID-19 in patients in a repeatable and cost effective way. Previous work has used public datasets of POCUS videos to train an AI model for diagnosis that obtains high sensitivity. Due to the high stakes application we propose the use of robust and explainable techniques. We demonstrate experimentally that robust models have more stable predictions and offer improved interpretability. A framework of contrastive explanations based on adversarial perturbations is used to explain model predictions that aligns with human visual perception.

Compared to other major medical imaging modalities such as X-ray, computed tomography (CT), and magnetic resonance imaging, medical ultrasound (US) has unique attributes that make it the preferred modality for many clinical applications. In particular, US is nonionizing, portable, and provides real-time imaging, with adequate spatial and depth resolution to visualize tissue dynamics. The ability to measure Doppler information is also important, particularly for measuring blood flows. The small size of US transducers is a key attribute for intravascular applications. In addition, accessibility has been increased with the use of portable US, which continues to move toward a smaller footprint and lower cost. Nowadays, some US probes can even be directly connected to a phone or tablet. On the other hand, US also has unique challenges, particularly in that image quality is highly dependent on the operator’s skill in acquiring images based on the proper position, orientation, and probe pressure. Additional challenges that further require operator skill include the presence of noise, artifacts, limited field of view, difficulty in imaging structures behind bone and air, and device variability across manufacturers. Sonographers become highly proficient through extensive training and long experience, but high intra- and interobserver variability remains. This skill dependence has limited the wider use of US by healthcare providers who are not US imaging specialists. Recent advances in machine learning (ML) have been increasingly applied to medical US (Brattain, Telfer, Dhyani, Grajo, & Samir, 2018), with a goal of reducing intra- and interobserver variability as well as interpretation time. As progress toward these goals is made, US use by nonspecialists is expected to proliferate, including nurses at the bedside or medics in the field. The acceleration in ML applications for medical US can be seen from the increasing number of publications (Fig. 8.1) and Food and Drug Administration (FDA) approvals (Table 8.1) in the past few years. Fig. 8.1 shows that cardiovascular applications (spanning the heart, brain and vessels) have received the most attention, compared to other organs. Table 8.1 shows that pace of US FDA-cleared artificial intelligence (AI) products that combine AI and ultrasound is accelerating. Of note, many of the products have been approved over the last couple of years. Companies such as Butterfly Network (Guilford, CT) have also demonstrated AI-driven applications for portable ultrasound and more FDA clearances are expected to be published. The goals of this chapter are to highlight the recent progress, as well as the current challenges and future opportunities. Specifically, this chapter addresses topics such as the following: (1) what is the current state of machine learning for medical US application, both in research and commercially; (2) what applications are receiving the most attention and have performance improvements been quantified; (3) how do ML solutions fit in an overall workflow; and (4) what open-source datasets are available for the broader community to contribute to progress in this field. The focus is on cardiovascular applications (Section Cardiovascular/echocardiography), but common themes and differences for other applications for medical US are also summarized (Section Breast, liver, and thyroid ultrasound). A discussion is offered in Discussion and outlook section.

Multisystem Inflammatory Syndrome in Children (MIS-C) is appearing in infants, children, and young adults in association with COVID-19 (coronavirus disease 2019) infections of SARS-CoV-2. Kawasaki Disease (KD) is one of the most common vasculitides of childhood. KD presents with similar symptoms to MIS-C especially in severe forms such as Kawasaki Disease Shock Syndrome (KDSS). The observed symptoms for MIS-C and KD are consistent with Mast Cell Activation Syndrome (MCAS) characterized by inflammatory molecules released from activated mast cells. Based on the associations of KD with multiple viral and bacterial pathogens, we put forward the hypothesis that KD and MIS-C result from antibody activation of mast cells by Fc receptor-bound pathogen antibodies causing a hyperinflammatory response upon second pathogen exposure. Within this hypothesis, MIS-C may be atypical KD or a KD-like disease associated with SARS-CoV-2. We extend the mast cell hypothesis that increased histamine levels are inducing contraction of effector cells with impeded blood flow through cardiac capillaries. In some patients, pressure from impeded blood flow, within cardiac capillaries, may result in increased coronary artery blood pressure leading to aneurysms, a well-known complication in KD.

Background: In 80% of patients, COVID-19 presents as mild disease. 20% of cases develop severe (13%) or critical (6%) illness. More severe forms of COVID-19 present as clinical severe acute respiratory syndrome, but include a T-predominant lymphopenia, high circulating levels of proinflammatory cytokines and chemokines, accumulation of neutrophils and macrophages in lungs, and immune dysregulation including immunosuppression. Methods: All major SARS-CoV-2 proteins were characterized using an amino acid residue variation analysis method. Results predict that most SARS-CoV-2 proteins are evolutionary constrained, with the exception of the spike (S) protein extended outer surface. Results were interpreted based on known SARS-like coronavirus virology and pathophysiology, with a focus on medical countermeasure development implications. Findings: Non-neutralizing antibodies to variable S domains may enable an alternative infection pathway via Fc receptor-mediated uptake. This may be a gating event for the immune response dysregulation observed in more severe COVID-19 disease. Prior studies involving vaccine candidates for FCoV SARS-CoV-1 and Middle East Respiratory Syndrome coronavirus (MERS-CoV) demonstrate vaccination-induced antibody-dependent enhancement of disease (ADE), including infection of phagocytic antigen presenting cells (APC). T effector cells are believed to play an important role in controlling coronavirus infection; pan-T depletion is present in severe COVID-19 disease and may be accelerated by APC infection. Sequence and structural conservation of S motifs suggests that SARS and MERS vaccine ADE risks may foreshadow SARS-CoV-2 S-based vaccine risks. Autophagy inhibitors may reduce APC infection and T-cell depletion. Amino acid residue variation analysis identifies multiple constrained domains suitable as T cell vaccine targets. Evolutionary constraints on proven antiviral drug targets present in SARS-CoV-1 and SARS-CoV-2 may reduce risk of developing antiviral drug escape mutants. Interpretation: Safety testing of COVID-19 S protein-based B cell vaccines in animal models is strongly encouraged prior to clinical trials to reduce risk of ADE upon virus exposure.