Utilizing Wearable Device Data for Syndromic Surveillance: A Fever Detection Approach.

Commercially available wearable devices (wearables) show promise for continuous physiological monitoring. Previous works have demonstrated that wearables can be used to detect the onset of acute infectious diseases, particularly those characterized by fever. We aimed to evaluate whether these devices could be used for the more general task of syndromic surveillance. We obtained wearable device data (Oura Ring) from 63,153 participants. We constructed a dataset using participants' wearable device data and participants' responses to daily online questionnaires. We included days from the participants if they (1) completed the questionnaire, (2) reported not experiencing fever and reported a self-collected body temperature below 38 °C (negative class), or reported experiencing fever and reported a self-collected body temperature at or above 38 °C (positive class), and (3) wore the wearable device the nights before and after that day. We used wearable device data (i.e., skin temperature, heart rate, and sleep) from the nights before and after participants' fever day to train a tree-based classifier to detect self-reported fevers. We evaluated the performance of our model using a five-fold cross-validation scheme. Sixteen thousand, seven hundred, and ninety-four participants provided at least one valid ground truth day; there were a total of 724 fever days (positive class examples) from 463 participants and 342,430 non-fever days (negative class examples) from 16,687 participants. Our model exhibited an area under the receiver operating characteristic curve (AUROC) of 0.85 and an average precision (AP) of 0.25. At a sensitivity of 0.50, our calibrated model had a false positive rate of 0.8%. Our results suggest that it might be possible to leverage data from these devices at a public health level for live fever surveillance. Implementing these models could increase our ability to detect disease prevalence and spread in real-time during infectious disease outbreaks.

Elevated body temperature is associated with depressive symptoms: results from the TemPredict Study.

Correlations between altered body temperature and depression have been reported in small samples; greater confidence in these associations would provide a rationale for further examining potential mechanisms of depression related to body temperature regulation. We sought to test the hypotheses that greater depression symptom severity is associated with (1) higher body temperature, (2) smaller differences between body temperature when awake versus asleep, and (3) lower diurnal body temperature amplitude. Data collected included both self-reported body temperature (using standard thermometers), wearable sensor-assessed distal body temperature (using an off-the-shelf wearable sensor that collected minute-level physiological data), and self-reported depressive symptoms from > 20,000 participants over the course of ~ 7 months as part of the TemPredict Study. Higher self-reported and wearable sensor-assessed body temperatures when awake were associated with greater depression symptom severity. Lower diurnal body temperature amplitude, computed using wearable sensor-assessed distal body temperature data, tended to be associated with greater depression symptom severity, though this association did not achieve statistical significance. These findings, drawn from a large sample, replicate and expand upon prior data pointing to body temperature alterations as potentially relevant factors in depression etiology and may hold implications for development of novel approaches to the treatment of major depressive disorder.

Variability of temperature measurements recorded by a wearable device by biological sex.

BACKGROUND: Females have been historically excluded from biomedical research due in part to the documented presumption that results with male subjects will generalize effectively to females. This has been justified in part by the assumption that ovarian rhythms will increase the overall variance of pooled random samples. But not all variance in samples is random. Human biometrics are continuously changing in response to stimuli and biological rhythms; single measurements taken sporadically do not easily support exploration of variance across time scales. Recently we reported that in mice, core body temperature measured longitudinally shows higher variance in males than cycling females, both within and across individuals at multiple time scales. METHODS: Here, we explore longitudinal human distal body temperature, measured by a wearable sensor device (Oura Ring), for 6 months in females and males ranging in age from 20 to 79 years. In this study, we did not limit the comparisons to female versus male, but instead we developed a method for categorizing individuals as cyclic or acyclic depending on the presence of a roughly monthly pattern to their nightly temperature. We then compared structure and variance across time scales using multiple standard instruments. RESULTS: Sex differences exist as expected, but across multiple statistical comparisons and timescales, there was no one group that consistently exceeded the others in variance. When variability was assessed across time, females, whether or not their temperature contained monthly cycles, did not significantly differ from males both on daily and monthly time scales. CONCLUSIONS: These findings contradict the viewpoint that human females are too variable across menstrual cycles to include in biomedical research. Longitudinal temperature of females does not accumulate greater measurement error over time than do males and the majority of unexplained variance is within sex category, not between them.

Women are still excluded from research disproportionately, due in part to documented concerns that menstrual cycles make them more variable and so harder to study. In the past, we have challenged this claim, finding it does not hold for animal physiology, animal behavior, or human behavior. Here we are able to show that it does not hold in human physiology either. We analyzed 6 months of continuously collected temperature data measured by a commercial wearable device, in order to determine if it is true that females are more variable or less predictable than males. We found that temperatures mostly vary as a function of time of day and whether the individual was awake or asleep. Additionally, for some females, nightly maximum temperature contained a cyclical pattern with a period of around 28 days, consistent with menstrual cycles. The variability was different between cycling females, not cycling females, and males, but only cycling female temperature contained a monthly structure, making their changes more predictable than those of non-cycling females and males. We found the majority of unexplained variance to be within each sex/cycling category, not between them. All groups had indistinguishable measurement errors across time. This analysis of temperature suggests data-driven characteristics might be more helpful distinguishing individuals than historical categories such as binary sex. The work also supports the inclusion of females as subjects within biological research, as this inclusion does not weaken statistical comparisons, but does allow more equitable coverage of research results in the world.

Assessing Adherence to Multi-Modal Oura Ring Wearables From COVID-19 Detection Among Healthcare Workers.

Background Identifying early signs of a SARS-CoV-2 infection in healthcare workers could be a critical tool in reducing disease transmission. To provide this information, both daily symptom surveys and wearable device monitoring could have utility, assuming there is a sufficiently high level of participant adherence. Purpose The aim of this study is to evaluate adherence to a daily symptom survey and a wearable device (Oura Ring) among healthcare professionals (attending physicians and other clinical staff) and trainees (residents and medical students) in a hospital setting during the early stages of the COVID-19 pandemic. Methods In this mixed-methods observational study, the data were a subset (N=91) of those collected as part of the larger TemPredict Study. Demographic data analyses were conducted with descriptive statistics. Participant adherence to the wearable device protocol was reported as the percentage of days that sleep was recorded, and adherence to the daily survey was reported as the percentage of days with submitted surveys. Comparisons for the primary (wearable and survey adherence of groups) and secondary (adherence patterns among subgroups) outcomes were conducted using descriptive statistics, two-tailed independent t-tests, and Welch's ANOVA with post hoc analysis using Games-Howell. Results Wearable device adherence was significantly higher than the daily symptom survey adherence for most participants. Overall, participants were highly adherent to the wearable device, wearing the device an average of 87.8 ± 11.6% of study nights compared to survey submission, showing an average of 63.8 ± 27.4% of study days. In subgroup analysis, we found that healthcare professionals (HCPs) and medical students had the highest adherence to wearing the wearable device, while medical residents had lower adherence in both wearable adherence and daily symptom survey adherence. Conclusions These results indicated high participant adherence to wearable devices to monitor for impending infection in the course of a research study conducted as part of clinical practice. Subgroup analysis indicated HCPs and medical students maintained high adherence, but residents' adherence was lower, which is likely multifactorial, with differences in work demands and stress contributing to the findings. These results can guide the development of adherence strategies for a wearable device to increase the quality of data collection and assist in disease detection in this and future pandemics.

Modified Wavelet Analyses Permit Quantification of Dynamic Interactions Between Ultradian and Circadian Rhythms.

Circadian rhythms provide daily temporal structure to cellular and organismal biological processes, ranging from gene expression to cognition. Higher-frequency (intradaily) ultradian rhythms are similarly ubiquitous but have garnered far less empirical study, in part because of the properties that define them-multimodal periods, non-stationarity, circadian harmonics, and diurnal modulation-pose challenges to their accurate and precise quantification. Wavelet analyses are ideally suited to address these challenges, but wavelet-based measurement of ultradian rhythms has remained largely idiographic. Here, we describe novel analytical approaches, based on discrete and continuous wavelet transforms, which permit quantification of rhythmic power distribution across a broad ultradian spectrum, as well as precise identification of period within empirically determined ultradian bands. Moreover, the aggregation of normalized wavelet matrices allows group-level analyses of experimental treatments, thereby circumventing limitations of idiographic approaches. The accuracy and precision of these wavelet analyses were validated using in silico and in vivo models with known ultradian features. Experiments in male and female mice yielded robust and repeatable measures of ultradian period and power in home cage locomotor activity, confirming and extending reports of ultradian rhythm modulation by sex, gonadal hormones, and circadian entrainment. Seasonal changes in day length modulated ultradian period and power, and exerted opposite effects in the light and dark phases of the 24 h day, underscoring the importance of evaluating ultradian rhythms with attention to circadian phase. Sex differences in ultradian rhythms were more prominent at night and depended on gonadal hormones in male mice. Thus, relatively straightforward modifications to the wavelet procedure allowed quantification of ultradian rhythms with appropriate time-frequency resolution, generating accurate, and repeatable measures of period and power which are suitable for group-level analyses. These analytical tools may afford deeper understanding of how ultradian rhythms are generated and respond to interoceptive and exteroceptive cues.

Methods for detecting probable COVID-19 cases from large-scale survey data also reveal probable sex differences in symptom profiles.

Background: Daily symptom reporting collected via web-based symptom survey tools holds the potential to improve disease monitoring. Such screening tools might be able to not only discriminate between states of acute illness and non-illness, but also make use of additional demographic information so as to identify how illnesses may differ across groups, such as biological sex. These capabilities may play an important role in the context of future disease outbreaks. Objective: Use data collected via a daily web-based symptom survey tool to develop a Bayesian model that could differentiate between COVID-19 and other illnesses and refine this model to identify illness profiles that differ by biological sex. Methods: We used daily symptom profiles to plot symptom progressions for COVID-19, influenza (flu), and the common cold. We then built a Bayesian network to discriminate between these three illnesses based on daily symptom reports. We further separated out the COVID-19 cohort into self-reported female and male subgroups to observe any differences in symptoms relating to sex. We identified key symptoms that contributed to a COVID-19 prediction in both males and females using a logistic regression model. Results: Although the Bayesian model performed only moderately well in identifying a COVID-19 diagnosis (71.6% true positive rate), the model showed promise in being able to differentiate between COVID-19, flu, and the common cold, as well as periods of acute illness vs. non-illness. Additionally, COVID-19 symptoms differed between the biological sexes; specifically, fever was a more important symptom in identifying subsequent COVID-19 infection among males than among females. Conclusion: Web-based symptom survey tools hold promise as tools to identify illness and may help with coordinated disease outbreak responses. Incorporating demographic factors such as biological sex into predictive models may elucidate important differences in symptom profiles that hold implications for disease detection.

Metrics from Wearable Devices as Candidate Predictors of Antibody Response Following Vaccination against COVID-19: Data from the Second TemPredict Study.

There is significant variability in neutralizing antibody responses (which correlate with immune protection) after COVID-19 vaccination, but only limited information is available about predictors of these responses. We investigated whether device-generated summaries of physiological metrics collected by a wearable device correlated with post-vaccination levels of antibodies to the SARS-CoV-2 receptor-binding domain (RBD), the target of neutralizing antibodies generated by existing COVID-19 vaccines. One thousand, one hundred and seventy-nine participants wore an off-the-shelf wearable device (Oura Ring), reported dates of COVID-19 vaccinations, and completed testing for antibodies to the SARS-CoV-2 RBD during the U.S. COVID-19 vaccination rollout. We found that on the night immediately following the second mRNA injection (Moderna-NIAID and Pfizer-BioNTech) increases in dermal temperature deviation and resting heart rate, and decreases in heart rate variability (a measure of sympathetic nervous system activation) and deep sleep were each statistically significantly correlated with greater RBD antibody responses. These associations were stronger in models using metrics adjusted for the pre-vaccination baseline period. Greater temperature deviation emerged as the strongest independent predictor of greater RBD antibody responses in multivariable models. In contrast to data on certain other vaccines, we did not find clear associations between increased sleep surrounding vaccination and antibody responses.

Analysis of wearable time series data in endocrine and metabolic research.

Many hormones in the body oscillate with different frequencies and amplitudes, creating a dynamic environment that is essential to maintain health. In humans, disruptions to these rhythms are strongly associated with increased morbidity and mortality. While mathematical models can help us understand rhythm misalignment, translating this insight into personalised healthcare technologies requires solving additional challenges. Here, we discuss how combining minimally invasive, high-frequency biosampling technologies with wearable devices can assist the development of hormonal surrogates. We review bespoke algorithms that can help analyse multidimensional, noisy, time series data and identify wearable signals that could constitute clinical proxies of endocrine rhythms. These techniques can support the development of computational biomarkers to support the diagnosis and management of endocrine and metabolic conditions.

Lower variability in female students than male students at multiple timescales supports the use of sex as a biological variable in human studies.

BACKGROUND: Men have been, and still are, included in more studies than women, in large part because of the lingering belief that ovulatory cycles result in women showing too much variability to be economically viable subjects. This belief has scientific and social consequences, and yet, it remains largely untested. Recent work in rodents has shown either that there is no appreciable difference in overall variability across a wealth of traits, or that in fact males may show more variability than females. METHODS: We analyzed learning management system logins associated to gender records spanning 2 years from 13,777 students at Northeastern Illinois University. These data were used to assess variability in daily rhythms in a heterogeneous human population. RESULTS: At the population level, men are more likely than women to show extreme chronotypes (very early or very late phases of activity). Men were also found to be more variable than women across and within individuals. Variance correlated negatively with academic performance, which also showed a gender difference. Whereas a complaint against using female subjects is that their variance is the driver of statistical sex differences, only 6% of the gender performance difference is potentially accounted for by variance, suggesting that variability is not the driver of sex differences here. CONCLUSIONS: Our findings do not support the idea that women are more behaviorally variable than men and may support the opposite. Our findings support including sex as a biological variable and do not support variance-based arguments for the exclusion of women as research subjects.

Maternal stress during pregnancy alters fetal cortico-cerebellar connectivity in utero and increases child sleep problems after birth.

Child sleep disorders are increasingly prevalent and understanding early predictors of sleep problems, starting in utero, may meaningfully guide future prevention efforts. Here, we investigated whether prenatal exposure to maternal psychological stress is associated with increased sleep problems in toddlers. We also examined whether fetal brain connectivity has direct or indirect influence on this putative association. Pregnant women underwent fetal resting-state functional connectivity MRI and completed questionnaires on stress, worry, and negative affect. At 3-year follow-up, 64 mothers reported on child sleep problems, and in the subset that have reached 5-year follow-up, actigraphy data (N = 25) has also been obtained. We observe that higher maternal prenatal stress is associated with increased toddler sleep concerns, with actigraphy sleep metrics, and with decreased fetal cerebellar-insular connectivity. Specific mediating effects were not identified for the fetal brain regions examined. The search for underlying mechanisms of the link between maternal prenatal stress and child sleep problems should be continued and extended to other brain areas.

Feasibility of continuous fever monitoring using wearable devices.

Elevated core temperature constitutes an important biomarker for COVID-19 infection; however, no standards currently exist to monitor fever using wearable peripheral temperature sensors. Evidence that sensors could be used to develop fever monitoring capabilities would enable large-scale health-monitoring research and provide high-temporal resolution data on fever responses across heterogeneous populations. We launched the TemPredict study in March of 2020 to capture continuous physiological data, including peripheral temperature, from a commercially available wearable device during the novel coronavirus pandemic. We coupled these data with symptom reports and COVID-19 diagnosis data. Here we report findings from the first 50 subjects who reported COVID-19 infections. These cases provide the first evidence that illness-associated elevations in peripheral temperature are observable using wearable devices and correlate with self-reported fever. Our analyses support the hypothesis that wearable sensors can detect illnesses in the absence of symptom recognition. Finally, these data support the hypothesis that prediction of illness onset is possible using continuously generated physiological data collected by wearable sensors. Our findings should encourage further research into the role of wearable sensors in public health efforts aimed at illness detection, and underscore the importance of integrating temperature sensors into commercially available wearables.

Evidence for a Coupled Oscillator Model of Endocrine Ultradian Rhythms.

Whereas long-period temporal structures in endocrine dynamics have been well studied, endocrine rhythms on the scale of hours are relatively unexplored. The study of these ultradian rhythms (URs) has remained nascent, in part, because a theoretical framework unifying ultradian patterns across systems has not been established. The present overview proposes a conceptual coupled oscillator network model of URs in which oscillating hormonal outputs, or nodes, are connected by edges representing the strength of node-node coupling. We propose that variable-strength coupling exists both within and across classic hormonal axes. Because coupled oscillators synchronize, such a model implies that changes across hormonal systems could be inferred by surveying accessible nodes in the network. This implication would at once simplify the study of URs and open new avenues of exploration into conditions affecting coupling. In support of this proposed framework, we review mammalian evidence for (1) URs of the gut-brain axis and the hypothalamo-pituitary-thyroid, -adrenal, and -gonadal axes, (2) UR coupling within and across these axes; and (3) the relation of these URs to body temperature. URs across these systems exhibit behavior broadly consistent with a coupled oscillator network, maintaining both consistent URs and coupling within and across axes. This model may aid the exploration of mammalian physiology at high temporal resolution and improve the understanding of endocrine system dynamics within individuals.

Artifact Rejection Methodology Enables Continuous, Noninvasive Measurement of Gastric Myoelectric Activity in Ambulatory Subjects.

The increasing prevalence of functional and motility gastrointestinal (GI) disorders is at odds with bottlenecks in their diagnosis, treatment, and follow-up. Lack of noninvasive approaches means that only specialized centers can perform objective assessment procedures. Abnormal GI muscular activity, which is coordinated by electrical slow-waves, may play a key role in symptoms. As such, the electrogastrogram (EGG), a noninvasive means to continuously monitor gastric electrical activity, can be used to inform diagnoses over broader populations. However, it is seldom used due to technical issues: inconsistent results from single-channel measurements and signal artifacts that make interpretation difficult and limit prolonged monitoring. Here, we overcome these limitations with a wearable multi-channel system and artifact removal signal processing methods. Our approach yields an increase of 0.56 in the mean correlation coefficient between EGG and the clinical "gold standard", gastric manometry, across 11 subjects (p < 0.001). We also demonstrate this system's usage for ambulatory monitoring, which reveals myoelectric dynamics in response to meals akin to gastric emptying patterns and circadian-related oscillations. Our approach is noninvasive, easy to administer, and has promise to widen the scope of populations with GI disorders for which clinicians can screen patients, diagnose disorders, and refine treatments objectively.

3.4 million real-world learning management system logins reveal the majority of students experience social jet lag correlated with decreased performance.

Misalignments between endogenous circadian rhythms and the built environment (i.e., social jet lag, SJL) result in learning and attention deficits. Currently, there is no way to assess the impact of SJL on learning outcomes of large populations as a response to schedule choices, let alone to assess which individuals are most negatively impacted by these choices. We analyzed two years of learning management system login events for 14,894 Northeastern Illinois University (NEIU) students to investigate the capacity of such systems as tools for mapping the impact of SJL over large populations while maintaining the ability to generate insights about individuals. Personal daily activity profiles were validated against known biological timing effects, and revealed a majority of students experience more than 30 minutes of SJL on average, with greater amplitude correlating strongly with a significant decrease in academic performance, especially in people with later apparent chronotypes. Our findings demonstrate that online records can be used to map individual- and population-level SJL, allow deep mining for patterns across demographics, and could guide schedule choices in an effort to minimize SJL's negative impact on learning outcomes.

Maternal and Early-Life Circadian Disruption Have Long-Lasting Negative Consequences on Offspring Development and Adult Behavior in Mice.

Modern life involves chronic circadian disruption through artificial light and these disruptions are associated with numerous mental and physical health maladies. Because the developing nervous system is particularly vulnerable to perturbation, we hypothesized that early-life circadian disruption would negatively impact offspring development and adult function. Pregnant mice were subjected to chronic circadian disruption from the time of uterine implantation through weaning. To dissociate in utero from postnatal effects, a subset of litters was cross-fostered at birth from disrupted dams to control dams and vice versa. Postnatal circadian disruption was associated with reduced adult body mass, social avoidance, and hyperactivity. In utero disruption resulted in more pronounced social avoidance and hyperactivity, phenotypes not abrogated by cross-fostering to control mothers. To examine whether circadian disruption affects development by acting as an early life stressor, we examined birthweight, litter size, maternal cannibalism, and epigenetic modifications. None of these variables differed between control and disrupted dams, or resembled patterns seen following early-life stress. Our findings indicate that developmental chronic circadian disruption permanently affects somatic and behavioral development in a stage-of-life-dependent manner, independent of early life stress mechanisms, underscoring the importance of temporal structure during development, both in utero and early postnatal life.

Sex differences in variability across timescales in BALB/c mice.

BACKGROUND: Females are markedly underinvestigated in the biological and behavioral sciences due to the presumption that cyclic hormonal changes across the ovulatory cycle introduce excess variability to measures of interest in comparison to males. However, recent analyses indicate that male and female mice and rats exhibit comparable variability across numerous physiological and behavioral measures, even when the stage of the estrous cycle is not considered. Hormonal changes across the ovulatory cycle likely contribute cyclic, intra-individual variability in females, but the source(s) of male variability has, to our knowledge, not been investigated. It is unclear whether male variability, like that of females, is temporally structured and, therefore, quantifiable and predictable. Finally, whether males and females exhibit variability on similar time scales has not been explored. METHODS: These questions were addressed by collecting chronic, high temporal resolution locomotor activity (LA) and core body temperature (CBT) data from male and female BALB/c mice. RESULTS: Contrary to expectation, males are more variable than females over the course of the day (diel variability) and exhibit higher intra-individual daily range than females in both LA and CBT. Between mice of a given sex, variability is comparable for LA but the inter-individual daily range in CBT is greater for males. To identify potential rhythmic processes contributing to these sex differences, we employed wavelet transformations across a range of periodicities (1-39 h). CONCLUSIONS: Although variability in circadian power is comparable between the sexes for both LA and CBT, infradian variability is greater in females and ultradian variability is greater in males. Thus, exclusion of female mice from studies because of estrous cycle variability may increase variance in investigations where only male measures are collected over a span of several hours and limit generalization of findings from males to females.