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Thyrotoxicosis is a common disease caused by an excess of thyroid hormones. The prevalence of thyrotoxicosis about 2% and 70-90% of thyrotoxicosis cases are caused by Graves' disease, an autoimmune disease, which has a high recurrence rate when treated with antithyroid drugs such as methimazole or propylthiouracil. The clinical symptoms and signs of thyrotoxicosis include palpitation, weight loss, restlessness, and difficulty sleeping. Although these clinical changes in thyrotoxicosis can be detected by currently available wearable activity trackers, there have been few trials of the clinical application of wearable devices in patients with thyrotoxicosis.
The aim of this study is to investigate the clinical applicability of wearable device-generated data to the management of thyrotoxicosis. We are analyzing continuously monitored data for heart rate, physical activity, and sleep in patients with thyrotoxicosis during their clinical course after treatment.
Thirty thyrotoxic patients and 10 control subjects were enrolled in this study at Seoul National University Bundang Hospital. Heart rate, physical activity, and sleep are being monitored using a Fitbit Charge HR or Fitbit Charge 2. Clinical data including anthropometric measures, thyroid function test, and hyperthyroidism symptom scale are recorded.
Study enrollment began in December 2016, and the intervention and follow-up phases are ongoing. The results of the data analysis are expected to be available by September 2017.
This study will provide a foundational feasibility trial of the clinical applications of biosignal measurements to the differential diagnosis, prediction of clinical course, early detection of recurrence, and treatment in patients with thyrotoxicosis.
ClinicalTrials.gov NCT03009357; https://clinicaltrials.gov/ct2/show/NCT03009357 (Archived by WebCite at http://www.webcitation.org/6wh4MWPm2)
Thyrotoxicosis is clinical term that refers collectively to all symptoms that occur when an excess of thyroid hormones (free thyroxine [T4] and/or free triiodothyronine [T3]) is supplied to the peripheral tissues. The term “hyperthyroidism” is used in a similar way and refers to thyrotoxicosis caused by excessive production and secretion of thyroid hormone from the thyroid gland. Thyrotoxicosis is caused by hyperthyroidism, but it can occur without hyperthyroidism. Graves’ disease is an organ-specific autoimmune disease in which autoantibodies to thyroid-stimulating hormone receptors stimulate the thyroid gland, which causes hyperthyroidism. The prevalence of thyrotoxicosis is about 2%, and 70-90% of cases are caused by Graves’ disease, although the rates and causes vary between different geographic areas [
Excess thyroid hormone affects many different organ systems. The clinical symptoms signs are fatigue, anxiety, palpitations, sweating, heat intolerance, anxiety, disturbed sleep, and weight loss [
Wearable activity trackers have grown in popularity over the past few years. The American College of Sports Medicine survey of fitness trends reported that wearable technology was the top-rated trend for 2016 [
The aim of this trial is to investigate whether changes in symptoms and signs of thyrotoxicosis, such as heart rate, physical activity, and sleep pattern, can be monitored by wearable devices during the course of thyrotoxicosis and whether these have clinical applications.
This is a single-centered, prospective observational study to analyze the changes in heart rate, physical activity, and sleep patterns monitored by commercially available wearable devices during the clinical course of thyrotoxicosis. Subjects have been recruited from the outpatient clinic of the endocrinology department at Seoul National University Bundang Hospital (SNUBH). Among those with newly diagnosed or recurrent thyrotoxicosis, we have included 30 patients who met the inclusion criteria. Ten healthy age- and sex-matched volunteers were also included as a control group.
Inclusion and exclusion criteria for patient and control groups.
Group | Inclusion criteria | Exclusion criteria |
Patients | Aged 15-60 years Diagnosed with newly developed or recurrent thyrotoxicosis Who can use a wearable device and smartphone apps Planned to be treated with ATDs if affected by Graves’ disease |
A history of thyrotoxic periodic paralysis Thyrotoxicosis caused by toxic nodular goiter Taking medications that can affect heart rate (except short-acting beta-blockers prescribed to relieve thyrotoxic symptoms) |
Controls | Aged 15-60 years Confirmed euthyroid state by TFT Who can use a wearable device and smartphone apps |
A history of thyroid disease or taking thyroid hormone or an ATD Taking medications that can affect heart rate |
aATD: antithyroid drug
bTFT: thyroid function test
The inclusion criteria for enrolment are listed in
The healthy control group included euthyroid people who have no history of thyroid disease. We recruited the control group from SNUBH staff and confirmed that they had no history of thyroid disease and no abnormal findings or medications that can affect heart rate through their medical history, which included employee health examinations and an interview.
When patients or controls visited the clinic and agreed to participate in this study, we explained how to use and manage the wearable device (eg, synchronization, charging, basic settings), download and install smartphone apps, and create an account. We then check that they can use and manage their devices by letting them repeat all processes mentioned above.
This protocol has been approved by the SNUBH Institutional Review Board (IRB #: B-1609-363-004) and is registered at ClinicalTrials.gov (trial registration number NCT03009357). The study design is displayed in
Blood tests include a thyroid function test, serum levels of antithyroid-stimulating hormone receptor antibody, and other biochemical tests. Tc-99m is used in the thyroid scan. P/Ex, physical examination; HSS, hyperthyroidism symptom scale; ATD, antithyroid drug.
The potential candidates of this study are patients with newly detected or recurrent thyrotoxicosis who meet the eligibility criteria. They are provided with a device and given brief on-site instructions for using the device and app, which is installed on their own smartphone. They are instructed to wear the device as much as possible throughout the day including when asleep. We also explain that if they do not wear the device or sync to the app for more than 5 days in a row, they will be excluded from the study because of poor compliance. After 1 to 2 weeks of screening period, the patients visit the clinic to confirm the results of the thyroid function test (TFT) and other tests to distinguish the cause (eg, autoantibodies, thyroid scan) and to start treatment according to the cause of thyrotoxicosis. At this point, patients are finally enrolled, and the study period starts.
Patients with Graves’ disease are prescribed a specific dose of an ATD as decided by the physician. Patients with transient thyrotoxicosis caused by thyroiditis are provided reassurance that the symptoms and signs are benign and self-limited. Patients taking a beta-blocker for control of symptoms, such as palpitations and tremor, are advised to take the drug when the symptoms are severe and to inform the investigator the dose and timing of the drug, which are recorded in the care report form (CRF). Regardless of the cause of thyrotoxicosis, all patients are being followed up once a month, when they undergo blood tests and a physical examination, complete the hyperthyroidism symptom scale (HSS), and have their anthropometric parameters measured. The ATD dose is adjusted as necessary. The study will end after the third visit for each patient. At the discretion of the attending physician and if the patient agrees, the duration of this observational study may be extended if thyroid function is not fully restored. Additional consent for extension of the study period is not necessary because it is already specified in the initial consent form.
Healthy adults have been recruited as a control group through an official announcement in SNUBH. The controls visit the hospital on the same schedule as the patients with thyrotoxicosis. They are provided the same instructions as the patients about using the device and apps installed on their own smartphone, and the importance of compliance. They also undergo the same blood tests as the patients and are instructed to inform the investigator if there is any change in their medication; this information is recorded in the CRF.
After the research process is completed, the subjects who were not excluded from the study during the study observation period will be allowed to keep the device.
Study design and flow.Blood tests include a thyroid function test, serum levels of antithyroid-stimulating hormone receptor antibody, and other biochemical tests. Tc-99m is used in the thyroid scan. P/Ex, physical examination; HSS, hyperthyroidism symptom scale; ATD, antithyroid drug.
To assess the clinical status of hyperthyroidism, the endocrinologist in charge of this study evaluated the patients using the HSS [
We are using the Fitbit charge HR or Fitbit charge 2 (Fitbit, San Francisco, CA, USA) and Fitbit apps for iOS or Android. The firmware version of this app is currently 18.122 and this latest version has been maintained continuously over the observation period.
During the study period and with the patient’s consent, each participant’s account information from the Fitbit app, including identification number and password, are shared with researchers, which allows researchers to access the account of Fitbit website [
Height and weight are measured with the subject in light clothing and without shoes to the nearest 0.1 cm and 0.1 kg, respectively. Body mass index is calculated as the ratio of weight and to the square of height (expressed in kilograms per square meter). Blood pressure and heart rate were measured on the right arm with the subject in a seated position. Serum levels of blood urea nitrogen, creatinine and glucose were measured by automated standard laboratory methods (Hitachi 747; Hitachi, Tokyo, Japan). Serum total protein, albumin, total bilirubin, alkaline phosphatase, aspartate aminotransferase, and alanine aminotransferase were measured with an autoanalyzer (TBA-200FR; Toshiba, Tokyo, Japan). For TFT, concentrations of serum T4 (DiaSorin, Saluggia, Italy) and thyroid-stimulating hormone (TSH; CIS Bio International, Gif-sur-Yvette, France) were measured using immunoradiometric assays. The free T4 assay had an analytical sensitivity of 0.05 ng/dl, while that for TSH had an analytical sensitivity of 0.04 mIU/l and a functional sensitivity of 0.07 mIU/l. The reference ranges for free T4 and TSH were 0.89-1.79 ng/dl and 0.3-4.0 mIU/l, respectively. Thyrotoxicosis was defined based on the results of the TFT: that is, overt thyrotoxicosis was defined as high free T4 and low TSH, and subclinical thyrotoxicosis as normal free T4 and low TSH. All subjects were examined for the presence of anti-TSH receptor antibody by radioimmunoassay (Cis Bio International) and the cutoff for positivity was >1.0 U/ml.
The primary goal of this study is to verify the changes in heart rate, physical activity, and sleep-related values generated from wearable devices during the clinical course of thyrotoxicosis. We will compare these device-generated data with conventionally evaluated symptoms and signs and analyze the relationships between each parameter and disease status.
Using the heart rate data recorded by the device and provided by the Fitbit database mentioned below, we will analyze all summary and detailed heart rate data including resting heart rate for the study duration.
We will analyze all summary and detailed data for physical activity, including total steps per day and total moving distance per day in both the horizontal and vertical directions.
We will analyze the sleep data including total time asleep, total number and time of awakening, and sleep efficiency, which is calculated as the total time asleep divided by the total time in bed. We will also assess the data for “minutes to fall asleep” using the app mentioned above.
We can download interday summary and intraday detailed data for heart rate, physical activity, and sleep from the Fitbit database in JSON format using an app programming interface which is provided by Fitbit [
To compare variables between the patient and control groups, we will use the Mann–Whitney test or Student’s
Examples of downloaded heart rate data. Summary.
Examples of downloaded heart rate data. Intraday.
Study enrollment began in December 2016. The recruitment of the patient group was completed, and two of the total 30 patients were excluded. One discontinued the study because of a skin reaction to the device (Fitbit Charge HR) on the wrist, and one patient was dropped from the study because of poor compliance in using the device. The remaining 28 patients and all controls completed the study. The data collection process was completed by August 2017. We expect to report the data analysis results in early 2018.
In this prospective, observational study, we will investigate the clinical applicability of wearable device-generated data to the management of thyrotoxicosis by analyzing continuously monitored data for heart rate, physical activity, and sleep for patients with thyrotoxicosis during their clinical course after treatment.
Monitoring heart rate in patients with thyrotoxicosis is required because palpitations or tachycardia are among the most common symptoms of thyrotoxicosis [
Abnormalities in sleep regulation often occur in patients with thyrotoxicosis [
Patients with hyperthyroidism exhibit a characteristic resting tremor and self-reported increase in voluntary physical activity, heat intolerance, and weight loss [
The major strength of this study is that it is the first study to monitor heart rate, physical activity, and sleep throughout the day using commercially available wearable devices in patients with thyrotoxicosis. This study also has some important clinical implications. We expect that the data derived from the continuous monitoring of these clinical parameters will be useful for the differential diagnosis of thyrotoxicosis. The two most common causes of thyrotoxicosis are Graves’ disease and thyroiditis. Although the clinical symptoms and signs tend to be more abrupt in patients with thyroiditis, clinically it is difficult to distinguish these through conventional interviews and physical examination. Therefore, continuously collected “high-definition data” should help to differentiate the clinical presentation according to the cause of thyrotoxicosis. If so, this will save time and cost in not having to perform the biochemical and radiological tests currently needed to make the differential diagnosis.
We also expect that these high-definition data may be useful for predicting the therapeutic response and clinical course. After starting the medication, patients must repeat blood testing for thyroid hormone levels every 1 or 2 months. If the dose of medication is insufficient or the disease is unresponsive to the medical treatment, the patient must endure the clinical symptoms until the next visit. Ideally, more frequent tests will provide more detailed information about the clinical course, but more frequent tests also inconvenience the patient and add to the cost. Being able to monitor the clinical course using biosignals from wearable devices may provide patients with faster and more accurate interventions during the treatment and follow-up process. In addition, if these detailed clinical parameters accurately reflect the changes in thyroid function, we expect that the recurrence of thyrotoxicosis may be detected earlier. We hope that the results of this study will allow us to develop apps to calculate the real-time risk of thyrotoxicosis for patients who discontinue their medication and therefore encourage the patient to attend the clinic promptly to receive the diagnosis of and treatment for recurrent thyrotoxicosis.
There are some limitations, which should be considered when interpreting the results. First, to control their symptoms, about 50% of the patients with thyrotoxicosis have been prescribed the nonselective beta-blocker propranolol with a relatively short duration of action. However, patients in the current study who have been prescribed medications have so far reported that they have not taken it continuously for more than 1 day; the drug’s maximum effects appear 60-90 minutes after oral administration [
The technologies to measure and analyze biosignals have not been developed fully, but have been extended from specific medical uses, such as in intensive care units or surgical monitoring, to everyday life. This evolution of technologies will eventually allow for easy, effective, and continuous monitoring of chronic diseases. Thyrotoxicosis changes various biosignals including heart rate and physical activity through the effect of excessive thyroid hormone. Currently available commercial wearable devices are expected to detect these changes in biosignals in thyrotoxic patients. We expect our study to provide clinical evidence of the usefulness of wearable devices for managing thyrotoxicosis.
antithyroid drug
case report form
generalized estimating equation
hyperthyroidism symptom scale
Seoul National University Bundang Hospital
triiodothyronine
thyroxine
thyroid function test
thyroid hormone stimulating hormone
This research was supported by a research grant (02-2016-035) from the Seoul National University Bundang Hospital to JHM
None declared
JEL and JHM designed the study. JEL, JHM, DHL, TJO, KMK, SHC, SL, YJP, DJP, and HCK contributed data interpretation. JEL and JHM collected and analyzed the data. JEL and JHM drafted the manuscript. All authors agreed on the final content of the manuscript.