Erick Andres Perez Alday

Background: Posttraumatic stress disorder (PTSD) causes heightened fight-or-flight responses to traumatic memories (i.e., hyperarousal). Although hyperarousal is hypothesized to cause irregular breathing (i.e., respiratory variability), no quantitative markers of respiratory variability have been shown to correspond with PTSD symptoms in humans. Objective: In this study, we define interpretable markers of respiration pattern variability (RPV) and investigate whether these markers respond during traumatic memories, correlate with PTSD symptoms, and differ in patients with PTSD. Methods: We recruited 156 veterans from the Vietnam-Era Twin Registry to participate in a trauma recall protocol. From respiratory effort and electrocardiogram measurements, we extracted respiratory timings and rate using a robust quality assessment and fusion approach. We then quantified RPV using the interquartile range and compared RPV between baseline and trauma recall conditions, correlated PTSD symptoms to the difference between trauma recall and baseline RPV (i.e., $\Delta$ RPV), and compared $\Delta$ RPV between patients with PTSD and trauma-exposed controls. Leveraging a subset of 116 paired twins, we then uniquely controlled for factors shared by co-twins via within-pair analysis for further validation. Results: We found RPV was increased during traumatic memories (p $< $ .001), $\Delta$ RPV was positively correlated with PTSD symptoms (p $< $ .05), and patients with PTSD exhibited higher $\Delta$ RPV than trauma-exposed controls (p $< $ .05). Conclusions: This paper is the first to elucidate RPV markers that respond during traumatic memories, especially in patients with PTSD, and correlate with PTSD symptoms. Significance: These findings encourage future studies outside the clinic, where interpretable markers of respiratory variability are used to track hyperarousal.

Background: Autonomic function can be measured noninvasively using heart rate variability (HRV), which indexes overall sympathovagal balance. Deceleration capacity (DC) of heart rate is a more specific metric of vagal modulation. Higher values of these measures have been associated with reduced mortality risk primarily in patients with cardiovascular disease, but their significance in community samples is less clear. Methods and Results: This prospective twin study followed 501 members from the VET (Vietnam Era Twin) registry. At baseline, frequency domain HRV and DC were measured from 24‐hour Holter ECGs. During an average 12‐year follow‐up, all‐cause death was assessed via the National Death Index. Multivariable Cox frailty models with random effect for twin pair were used to examine the hazard ratios of death per 1‐SD increase in log‐transformed autonomic metrics. Both in the overall sample and comparing twins within pairs, higher values of low‐frequency HRV and DC were significantly associated with lower hazards of all‐cause death. In within‐pair analysis, after adjusting for baseline factors, there was a 22% and 27% lower hazard of death per 1‐SD increment in low‐frequency HRV and DC, respectively. Higher low‐frequency HRV and DC, measured during both daytime and nighttime, were associated with decreased hazard of death, but daytime measures showed numerically stronger associations. Results did not substantially vary by zygosity. Conclusions: Autonomic inflexibility, and especially vagal withdrawal, are important mechanistic pathways of general mortality risk, independent of familial and genetic factors.

Post‐traumatic stress disorder (PTSD) is an independent risk factor for incident heart failure, but the underlying cardiac mechanisms remained elusive. Impedance cardiography (ICG), especially when measured during stress, can help understand the underlying psychophysiological pathways linking PTSD with heart failure. We investigated the association between PTSD and ICG‐based contractility metrics (pre‐ejection period (PEP) and Heather index (HI)) using a controlled twin study design with a laboratory‐based traumatic reminder stressor. PTSD status was assessed using structured clinical interviews. We acquired synchronized electrocardiograms and ICG data while playing personalized‐trauma scripts. Using linear mixed‐effects models, we examined twins as individuals and within PTSD‐discordant pairs. We studied 137 male veterans (48 pairs, 41 unpaired singles) from Vietnam War Era with a mean (standard deviation) age of 68.5(2.5) years. HI during trauma stress was lower in the PTSD vs. non‐PTSD individuals (7.2 vs. 9.3 [ohm/s²], p = .003). PEP reactivity (trauma minus neutral) was also more negative in PTSD vs. non‐PTSD individuals (−7.4 vs. −2.0 [ms], p = .009). The HI and PEP associations with PTSD persisted for adjusted models during trauma and reactivity, respectively. For within‐pair analysis of eight PTSD‐discordant twin pairs (out of 48 pairs), PTSD was associated with lower HI in neutral, trauma, and reactivity, whereas no association was found between PTSD and PEP. PTSD was associated with reduced HI and PEP, especially with trauma recall stress. This combination of increased sympathetic activation and decreased cardiac contractility combined may be concerning for increased heart failure risk after recurrent trauma re‐experiencing in PTSD.

Background: Heart failure (HF) is a major cause of frequent hospitalization and death. Early detection of HF symptoms using smartphone-based monitoring may reduce adverse events in a low-cost, scalable way. Objective: We examined the relationship of HF decompensation events with smartphone-based features derived from passively and actively acquired data. Methods: This was a prospective cohort study in which we monitored HF participants’ social and movement activities using a smartphone app and followed them for clinical events via phone and chart review and classified the encounters as compensated or decompensated by reviewing the provider notes in detail. We extracted motion, location, and social interaction passive features and self-reported quality of life weekly (active) with the short Kansas City Cardiomyopathy Questionnaire (KCCQ-12) survey. We developed and validated an algorithm for classifying decompensated versus compensated clinical encounters (hospitalizations or clinic visits). We evaluated models based on single modality as well as early and late fusion approaches combining patient-reported outcomes and passive smartphone data. We used Shapley additive explanation values to quantify the contribution and impact of each feature to the model. Results: We evaluated 28 participants with a mean age of 67 years (SD 8), among whom 11% (3/28) were female and 46% (13/28) were Black. We identified 62 compensated and 48 decompensated clinical events from 24 and 22 participants, respectively. The highest area under the precision-recall curve (AUCPr) for classifying decompensation was with a late fusion approach combining KCCQ-12, motion, and social contact features using leave-one-subject-out cross-validation for a 2-day prediction window. It had an AUCPr of 0.80, with an area under the receiver operator curve (AUC) of 0.83, a positive predictive value (PPV) of 0.73, a sensitivity of 0.77, and a specificity of 0.88 for a 2-day prediction window. Similarly, the 4-day window model had an AUC of 0.82, an AUCPr of 0.69, a PPV of 0.62, a sensitivity of 0.68, and a specificity of 0.87. Passive social data provided some of the most informative features, with fewer calls of longer duration associating with a higher probability of future HF decompensation. Conclusions: Smartphone-based data that includes both passive monitoring and actively collected surveys may provide important behavioral and functional health information on HF status in advance of clinical visits. This proof-of-concept study, although small, offers important insight into the social and behavioral determinants of health and the feasibility of using smartphone-based monitoring in this population. Our strong results are comparable to those of more active and expensive monitoring approaches, and underscore the need for larger studies to understand the clinical significance of this monitoring method.

Post‐traumatic stress disorder (PTSD) has been associated with cardiovascular disease (CVD), but the mechanisms remain unclear. Autonomic dysfunction, associated with higher CVD risk, may be triggered by acute PTSD symptoms. We hypothesized that a laboratory‐based trauma reminder challenge, which induces acute PTSD symptoms, provokes autonomic dysfunction in a cohort of veteran twins. We investigated PTSD‐associated real‐time physiologic changes with a simulation of traumatic experiences in which the twins listened to audio recordings of a one‐minute neutral script followed by a one‐minute trauma script. We examined two heart rate variability metrics: deceleration capacity (DC) and logarithmic low frequency (log‐LF) power from beat‐to‐beat intervals extracted from ambulatory electrocardiograms. We assessed longitudinal PTSD status with a structured clinical interview and the severity with the PTSD Symptoms Scale. We used linear mixed‐effects models to examine twin dyads and account for cardiovascular and behavioral risk factors. We examined 238 male Veteran twins (age 68 ± 3 years old, 4% black). PTSD status and acute PTSD symptom severity were not associated with DC or log‐LF measured during the neutral session, but were significantly associated with lower DC and log‐LF during the traumatic script listening session. Long‐standing PTSD was associated with a 0.38 (95% confidence interval, −0.83,‐0.08) and 0.79 (−1.30,‐0.29) standardized unit lower DC and log‐LF, respectively, compared to no history of PTSD. Traumatic reminders in patients with PTSD lead to real‐time autonomic dysregulation and suggest a potential causal mechanism for increased CVD risk, based on the well‐known relationships between autonomic dysfunction and CVD mortality.

Post-Traumatic Stress Disorder (PTSD) is a psychiatric condition resulting from threatening or horrifying events. We hypothesized that circadian rhythm changes, measured by a wrist-worn research watch are predictive of post-trauma outcomes. Approach: 1618 post-trauma patients were enrolled after admission to emergency departments (ED). Three standardized questionnaires were administered at week eight to measure post-trauma outcomes related to PTSD, sleep disturbance, and pain interference with daily life. Pulse activity and movement data were captured from a research watch for eight weeks. Standard and novel movement and cardiovascular metrics that reflect circadian rhythms were derived using this data. These features were used to train different classifiers to predict the three outcomes derived from week-eight surveys. Clinical surveys administered at ED were also used as features in the baseline models. Results: The highest cross-validated performance of research watch-based features was achieved for classifying participants with pain interference by a logistic regression model, with an area under the receiver operating characteristic curve (AUC) of 0.70. The ED survey-based model achieved an AUC of 0.77, and the fusion of research watch and ED survey metrics improved the AUC to 0.79. Significance: This work represents the first attempt to predict and classify post-trauma symptoms from passive wearable data using machine learning approaches that leverage the circadian desynchrony in a potential PTSD population.

Objective : Vast 12-lead ECGs repositories provide opportunities to develop new machine learning approaches for creating accurate and automatic diagnostic systems for cardiac abnormalities. However, most 12-lead ECG classification studies are trained, tested, or developed in single, small, or relatively homogeneous datasets. In addition, most algorithms focus on identifying small numbers of cardiac arrhythmias that do not represent the complexity and difficulty of ECG interpretation. This work addresses these issues by providing a standard, multi-institutional database and a novel scoring metric through a public competition: the PhysioNet/Computing in Cardiology Challenge 2020. Approach : A total of 66 361 12-lead ECG recordings were sourced from six hospital systems from four countries across three continents; 43 101 recordings were posted publicly with a focus on 27 diagnoses. For the first time in a public competition, we required teams to publish open-source code for both training and testing their algorithms, ensuring full scientific reproducibility. Main results : A total of 217 teams submitted 1395 algorithms during the Challenge, representing a diversity of approaches for identifying cardiac abnormalities from both academia and industry. As with previous Challenges, high-performing algorithms exhibited significant drops ( ≲ 10%) in performance on the hidden test data. Significance : Data from diverse institutions allowed us to assess algorithmic generalizability. A novel evaluation metric considered different misclassification errors for different cardiac abnormalities, capturing the outcomes and risks of different diagnoses. Requiring both trained models and code for training models improved the generalizability of submissions, setting a new bar in reproducibility for public data science competitions.

The subject of the PhysioNet/Computing in Cardiology Challenge 2020 was the identification of cardiac abnormalities in 12-lead electrocardiogram (ECG) recordings. A total of 66,405 recordings were sourced from hospital systems from four distinct countries and annotated with clinical diagnoses, including 43,101 annotated recordings that were posted publicly. For this Challenge, we asked participants to design working, open-source algorithms for identifying cardiac abnormalities in 12-lead ECG recordings. This Challenge provided several innovations. First, we sourced data from multiple institutions from around the world with different demographics, allowing us to assess the generalizability of the algorithms. Second, we required participants to submit both their trained models and the code for reproducing their trained models from the training data, which aids the generalizability and reproducibility of the algorithms. Third, we proposed a novel evaluation metric that considers different misclassification errors for different cardiac abnormalities, reflecting the clinical reality that some diagnoses have similar outcomes and varying risks. Over 200 teams submitted 850 algorithms (432 of which successfully ran) during the unofficial and official phases of the Challenge, representing a diversity of approaches from both academia and industry for identifying cardiac abnormalities. The official phase of the Challenge is ongoing.

Background: The risk of sudden cardiac death (SCD) is known to be dynamic. However, the accuracy of a dynamic SCD prediction is unknown. We aimed to measure the dynamic predictive accuracy of ECG biomarkers of SCD and competing non-sudden cardiac death (non-SCD).Methods: Atherosclerosis Risk In Community study participants with analyzable ECGs in sinus rhythm were included (n = 15,716; 55% female, 73% white, age 54.2 ± 5.8 y). ECGs of 5 follow-up visits were analyzed. Global electrical heterogeneity and traditional ECG metrics (heart rate, QRS, QTc) were measured. Adjudicated SCD was the primary outcome; non-SCD was the competing outcome. Time-dependent area under the receiver operating characteristic curve (ROC(t) AUC) analysis was performed to assess the prediction accuracy of a continuous biomarker in a period of 3,6,9 months, and 1,2,3,5,10, and 15 years using a survival analysis framework. Reclassification improvement as compared to clinical risk factors (age, sex, race, diabetes, hypertension, coronary heart disease, stroke) was measured.Results: Over a median 24.4 y follow-up, there were 577 SCDs (incidence 1.76 (95%CI 1.63–1.91)/1000 person-years), and 829 non-SCDs [2.55 (95%CI 2.37–2.71)]. No ECG biomarkers predicted SCD within 3 months after ECG recording. Within 6 months, spatial ventricular gradient (SVG) elevation predicted SCD (AUC 0.706; 95%CI 0.526–0.886), but not a non-SCD (AUC 0.527; 95%CI 0.303–0.75). SVG elevation more accurately predicted SCD if the ECG was recorded 6 months before SCD (AUC 0.706; 95%CI 0.526–0.886) than 2 years before SCD (AUC 0.608; 95%CI 0.515–0.701). Within the first 3 months after ECG recording, only SVG azimuth improved reclassification of the risk beyond clinical risk factors: 18% of SCD events were reclassified from low or intermediate risk to a high-risk category. QRS-T angle was the strongest long-term predictor of SCD (AUC 0.710; 95%CI 0.668–0.753 for ECG recorded within 10 years before SCD).Conclusion: Short-term and long-term predictive accuracy of ECG biomarkers of SCD differed, reflecting differences in transient vs. persistent SCD substrates. The dynamic predictive accuracy of ECG biomarkers should be considered for competing SCD risk scores. The distinction between markers predicting short-term and long-term events may represent the difference between markers heralding SCD (triggers or transient substrates) versus markers identifying persistent substrate.