Exploring the Link Between Exogenous Thyroid Hormones and Dementia Symptoms: A Real-World Disproportionality Analysis of FDA Adverse Event Reporting System

Abstract

Background:

A growing body of evidence indicates a strong association between exogenous thyroid hormone (ETH) and brain health. Establishing the potential relationship between ETH therapy and dementia symptoms is crucial for patients with thyroid disorders.

Objective:

In this study, we investigate the potential association between ETH therapy and dementia symptoms by exploring the Food and Drug Administration Adverse Event Reporting System (FAERS) database.

Methods:

Disproportionality analysis (DPA) was conducted using postmarketing data from the FAERS repository (Q1 2004 to Q4 2023). Cases of dementia symptoms associated with ETH therapy were identified and analyzed through DPA using reporting odds ratios and information component methods. Dose and time-to-onset analyses were performed to assess the association between ETH therapy and dementia symptoms.

Results:

A total of 9889 cases of ETH-associated symptoms were identified in the FAERS database. Dementia accounted for a consistent proportion of adverse drug reactions each year (3.4%-6.3%). The DPA indicated an association between ETH therapy and dementia symptoms, which remained significant even across sex, age, and indications. The median time-to-onset of dementia symptoms was 7.5 days, and the median treatment time was 40.5 days. No significant dose-response relationship was observed.

Conclusion and relevance:

This study provides evidence for a link between ETH therapy and dementia. Clinicians are therefore advised to exercise vigilance, conduct comprehensive monitoring, and consider individualized dosing to mitigate potential reactions to ETH drug administration.

Keywords

thyroid hormones dementia pharmacovigilance FAERS database thyroid disorders

Graphical abstract

Introduction

Thyroid hormones are primary endogenous hormones secreted by the thyroid gland. In response to thyroid-stimulating hormone release by the pituitary gland, a normally functioning thyroid gland will produce and secrete thyroxine (T4), which is then converted through deiodination into its active metabolite triiodothyronine (T3). While T4 is the primary product secreted by the thyroid gland, T3 exerts most of the physiological effects of the thyroid hormones.¹ T4 and T3 have a relative potency of 1:4 (T4:T3). Thyroid hormones profoundly affect almost all nucleated cells and play crucial roles in neuronal development, reproduction, and the regulation of energy metabolism.² Thyroid disorders have increased in frequency as a result of lifestyle changes, with hypothyroidism and hyperthyroidism now prevalent endocrine disorders worldwide.^3,4 Advances in clinical practice have driven improvements in the detection of thyroid disorders.⁵ In recent decades, the gradual lowering of the threshold for treatment and the increased use of sensitive thyroid function testing have resulted in a rise in the diagnosis of borderline or mild cases. This trend has triggered further discussions regarding additional treatments for subclinical thyroid disorders.^6-8

Exogenous thyroid hormones (ETHs), such as levothyroxine (L-T4) and T3, are often administered to patients for thyroid hormone replacement/adjuvant therapy.⁹ Exogenous thyroid hormones are among the most commonly prescribed medications in developed countries such as Europe and the United States, where their use is more aggressive.^6,10 However, the long-term use of ETHs is not without risks, and frequent occurrences of adverse drug reactions (ADRs) persist. In the labels, the most common ADRs include cardiovascular events, metabolic disturbances, and nervous system effects, which have an incidence of about 1% to 10%.⁹ Moreover, a growing body of evidence indicates a strong association between ETHs and brain health, with particular attention currently focused on ETH-associated dementia as a potential ADR.^11,12

Several studies have linked thyroid hormones to dementia symptoms.^13-16 For instance, a cohort study revealed that patients with hyperthyroidism faced a notably increased risk of all-cause dementia with each 6-month decrease in thyrotropin levels (hazard ratio: 1.16; 95% confidence interval: 1.12-1.22).¹³ In addition, a prospective, population-based cohort demonstrated that individuals with higher free thyroxine had a higher risk of dementia (hazard ratio: 1.04; 95% confidence interval: 1.01-1.07).¹⁶ Nonetheless, previous studies had limitations such as small sample sizes and short follow-up periods, leading to uncertainty regarding the implications for the use of ETHs. Therefore, to elucidate the relationship between ETHs and dementia symptoms, this study utilizes the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) to conduct a comprehensive and systematic data analysis. The FAERS database was designed to monitor postmarketing adverse reactions to pharmaceuticals and therapeutic biologics and includes extensive information on drug use and related adverse event reports.¹⁷ Through descriptive analyses, disproportionality analyses (DPAs), medication analyses, and other metrics, we aim to measure the association between ETH therapies and dementia symptoms with the goal of revealing the pathogenetic characteristics of this relationship. In addition, by reviewing existing studies, we aim to provide a more profound and comprehensive summary of this relationship. This study has important clinical implications for reducing the potential risk of dementia symptoms associated with ETH treatment.

Methods

Data Sources and Study Design

The FAERS is one of the most accessible global ADR databases. Raw quarterly data were accessed from the FDA website. Microsoft SQL Server (version 2019; Microsoft Corporation, Redmond, WA, USA) was used for data processing. Notably, ETHs were marketed before the inception of FAERS. Therefore, for a comprehensive analysis, we incorporated quarterly data spanning from FAERS initiation (Quarter 1, 2004) to the initiation of this study (Quarter 3, 2023). Given the potential for significant errors introduced by duplicate or implausible reports, as highlighted in previous studies, we conducted a thorough and comprehensive cleaning and normalization process.¹⁸ This diligence ensured the interpretability and reliability of the data. A detailed examination of this process is provided in Supplementary material 1, Figure S1.^19-21 Ethical approval was not required for this study as it hinged on de-identified publicly available data.

Definition of Cases and Drugs of Interest

In the FAERS database, ADRs are classified according to the Medical Dictionary for Regulatory Activities (MedDRA) terminology based on signs and symptoms, called preferred terms. The ADRs of interest included cognitive disorders, behavioral and psychiatric symptoms of dementia, and amnesia, which were uniformly attributed to a standardized MedDRA query (SMQ) level called “dementia” by MedDRA (version 26.0). The drugs of interest included FDA-approved ETHs: levothyroxine, liothyronine, and thyroid USP (dried and powdered thyroid glands from pigs).²² We included all cases in which ETHs were administered and were listed as primary or secondary suspected drugs for dementia symptoms.

Descriptive Analysis

We reported the distribution of ETH-associated ADRs across life systems and counted the top 30 ADRs with the highest number of reports (SMQ level). We then described the yearly reported number and percentage of ETH-associated dementia symptom and nondementia symptom ADRs. Patient demographics (age, sex, and reporter type) and clinical aspects (outcome, medication, and indication) were documented in the reports of dementia symptoms with ETHs.

Disproportionality Analysis

The following sequential approach was adopted to systematically address major confounders:

To comprehensively examine potential associations, an exploratory disproportionality approach was employed to compare ETHs with all other drugs reported in the FAERS database. Disproportionality occurs when a specific ADR is associated with a drug. To identify any potential positive signals, 2 widely recognized DPA methods were applied, namely the Reporting Odds Ratio (ROR) and Bayesian confidence propagation neural network of information components (ICs).^23,24 As spurious associations may arise in events with very low expected frequencies, a statistical shrinkage transformation was executed to ensure conservative results.^25,26 For detailed definitions of DPA and shrinkage transformation procedures for the ROR and IC, please refer to the Supplementary Material 1, sections 2 and 3.²⁷

Considering the inherent heterogeneity and potential reporting bias in the FAERS database, we performed a series of sensitivity analyses. First, using the indi_pt field (which represents the indication), we narrowed the analyzed data set to the following populations: the geriatric population, those with Parkinson-like events, those with central nervous system vascular disorders, and those with hyperglycemia/new-onset diabetes mellitus. Restricting the analyzed population in this way can mitigate indication bias.²⁸ In addition, given the potential bias that may exist with differences in reporters, sex, age, and indications, we performed subgroup analyses to provide a comprehensive measure of the robustness of positive signals. ROR₀₂₅ and IC₀₂₅ were calculated using the processed dataset to conduct sensitivity and subgroup analyses.

Dose and Initial Onset Time Analysis

Dose data were extracted from the DRUG and DEMO tables, where only cases with detailed dose and weight information were included in the dose analysis. Within the FAERS database, the DEMO table provides the onset times of ADRs (event_dt), whereas the THER table contains the start and end times of drug use (start_dt and end_dt, respectively). Duration of treatment is calculated when start and end times are available. Time-to-onset (TTO) is calculated when the start and the onset times of ADRs are available. To elucidate the latency of dementia symptoms associated with ETHs, we conducted a TTO analysis. This involved selecting the parametric distribution model with Weibull, where the shape parameter β characterizes this parametric distribution.²⁸ Additional details regarding the TTO analysis and the Weibull distribution model can be found in the Supplementary Material l , sections 4 and 5.²⁹

Global Assessment of Evidence

The Modified Bradford Hill Criteria were employed to evaluate potential relationships among the available evidence, including indicators such as strength, consistency, specificity, temporality, biological gradient, biological plausibility, ecological coherence, experimental evidence, and analogy.^30-32 Specifically, biological plausibility was assessed to determine whether a specific mechanism supports the potential relationship between ETH therapy and dementia symptoms. Moreover, we considered the strength of the evidence, gauged the magnitude of observed effects, and assessed the consistency of the findings across different studies or sources. Specificity was used to evaluate whether certain events were linked to specific factors, whereas coherence was employed to examine the temporal sequence of events that corresponded with a potential relationship. These indicators help evaluate the credibility of observational study results to determine potential relationships. Additional details regarding The Modified Bradford Hill Criteria can be found in the Supplementary Material l , Section 6.

Statistical Analysis

The DPA threshold of the reporting signal was defined as IC₀₂₅ > 0 and ROR₀₂₅ > 1. R software (version 4.3.2; R Foundation for Statistical Computing, Vienna, Austria) was used for plotting, TTO analysis, DPA calculations, and independent sample t-test analysis. All data were expressed as the median value (interquartile range, IQR). A P value <.05 was considered to represent a significant difference between the 2 groups. This study is reported as per the Strengthening the Reporting of Observational Studies in Epidemiology guideline.³³

Results

Descriptive Analysis Results

From 2004 quarter 1 to 2023 quarter 3, 59 680 cases with 327 869 reports of ETH-associated ADRs were identified from the FAERS database. In terms of the number of ADRs reported, the brain (N = 29 850), gastrointestinal tract (N = 26 210), muscles (N = 20 923), lungs (N = 16 122), and heart (N = 13 471) were the most likely sites of ADRs associated with the use of ETHs (Figure 1A). After categorization using the SMQ, the 5 most common ADRs were gastrointestinal dysfunction (N = 21 438), hypoglycemia (N = 20 886), noninfectious encephalopathy/delirium (N = 20 548), anticholinergic syndrome (N = 20 099), and dementia (N = 16 294) (Figure 1B). Although the reported number of dementia and nondementia symptom groups varies from year to year, dementia consistently accounted for a significant proportion of all ADRs throughout the study period (3.4%-6.3%, Figure 1C).

Demographic information was analyzed for 9889 cases with dementia symptoms. Table 1 shows the clinical characteristics of the patients. More than 80% of these reports were from the United States, France, and Canada. Approximately 32% of the cases were reported by health care professionals, such as physicians and pharmacists. Despite some reports with unknown or missing information on sex (8.33%), we observed a higher incidence of dementia symptoms in females than in males using ETHs (80.78% vs 10.89%). Among the available data, the median patient age was 57 years (IQR: 46-69 years). Adults accounted for most of the reports (43.75%), with relatively few reports for juvenile/seniors (1.36% and 23.28%, respectively). The most commonly reported ETHs were levothyroxine (93.22%), while hypothyroidism (32.31%) was the most frequently reported indication.

Table 1.

Cases Characteristics of EHTs-Associated Dementia Symptoms in the FAERS Database.

Characteristics	Report number, n	Report proportion, %
Number of reports	9889	/
Reported countries (top 3)
The United States	3553	35.93
France	3215	32.51
Canada	1336	13.51
Reporter^a
Health care professional	3209	32.45
Non-health care professional	6013	60.80
Unknown or missing	667	6.74
Sex
Male	1077	10.89
Female	7988	80.78
Unknown or missing	824	8.33
Age category, years
Juvenile (<18)	134	1.36
Adult (18-65)	4326	43.75
Seniors (>65)	2302	23.28
Unknown or missing	3127	31.62
Median (IQR)	57 (46-69)	/
Indication (top 5)
Hypothyroidism	3195	32.31
Thyroid disorder	688	6.96
Thyroiditis	677	6.85
Thyroidectomy	522	5.28
Hyperthyroidism	205	2.07
Medication
Levothyroxine	9219	93.22
Liothyronine	205	2.07
Thyroid USP	130	1.31
Polypharmacy^b	335	3.39
Serious outcome^c
Death	138	1.40
Life-threatening	478	4.83
Hospitalization	440	4.45
Disability	2569	25.98
Others	6739	68.15

Health care professional, including reporters such as physician, pharmacists, and so on; Non-health care professional, including reporters such as consumer, lawyer, and so on.

Simultaneous usage of multiple medications, including levothyroxine, liothyronine, and thyroid USP.

Since a case may experience different clinical outcomes during drug therapy, it is reasonable that the sum percentage of the outcome under this item may exceed 100%.

IQR, interquartile range.

DPA Results

First, a primary analysis was conducted to compare ETHs in different control group populations in the FAERS database. The evaluated control group populations were the total database population (ROR₀₂₅ = 2.64, IC₀₂₅ = 1.40), the geriatric population (ROR₀₂₅ = 2.48, IC₀₂₅ = 1.31), the population with Parkinson-like events (ROR₀₂₅ = 1.71, IC₀₂₅ = 0.78), the population with central nervous system vascular disorders (ROR₀₂₅ = 7.74, IC₀₂₅ = 2.97), and the population with hyperglycemia/new-onset diabetes mellitus (ROR₀₂₅ = 7.51, IC₀₂₅ = 2.91), which exhibited a signal of disproportionate reporting. After conducting further subgroup analyses, the DPA results for ETH-associated dementia symptoms were ROR₀₂₅ > 1 and IC₀₂₅ > 0 across reporter type, sex, age, and indications, indicating ADR signals (Figure 2).

Dose Analysis Results and TTO of Dementia Symptoms

Based on data availability, a total of 1863 dementia symptoms and 10 376 nondementia symptom cases were included in the dose analysis. For cases with dementia symptoms, the doses were not significantly higher than those in cases without dementia symptoms for ETHs, with the median (IQR) dose being 100 (50-125) and 100 (62.5-125) μg/q24h, respectively (Figure 3A). After accounting for body weight, the doses in the dementia (N = 806) and nondementia symptom (N = 4172) groups were 1.21 (0.64-1.63) and 1.27 (0.86-1.66) μg/kg/q24h, respectively (Figure 3B). The independent sample t-test showed a statistically significant difference between the 2 groups (P < .01). Based on data availability, a total of 1134 dementia symptoms were included in the TTO analysis. The median (IQR) latency period for developing dementia symptoms with the use of ETHs was 7.5 (0.5-41.5) days, and the median duration of treatment for these cases (N = 706) was 40.5 (2.5-143.5) days (Figure 3C). The Weibull distribution results showed β = 0.44 (0.42-0.46), which indicates that ETH-associated dementia symptoms were more likely to occur early in the medication period (Figure 3D).

Global Assessment of the Evidence

The Bradford Hill Criteria were met in this study, as evidenced by the robust disproportionality strength and consistent presence throughout the analyses. Coherence and biological plausibility further supported the probable association between ETH therapy and dementia symptoms (Table 2).

Table 2.

Global Assessment Through Adapted Bradford Hill Criteria.

Criteria	Description	Source/method
Strength of the association	Although DPA values are not measures of risk, the strength of the DPA value in all analyses suggests a positive ADR signal.	Disproportionality analysis
Analogy	DPA continues to show positive signals when compared in a different population context (including populations of geriatrics, with Parkinson-like events, with central nervous system vascular disorders, and with hyperglycemia/new-onset diabetes mellitus).	Disproportionality analysis and labels
Biological plausibility/empirical evidence	Raised thyroid hormone levels promote rapid metabolism and can trigger oxidative stress affecting the viability of neurons in patients, which may lead to dementia.^34,35 Some studies have shown an association between dementia and excess levels of T3 and T4, as well as elevated levels of T4 in patients with mild dementia.³⁶	References
Consistency	The DPA results were consistent in the subgroup analyses.	Disproportionality analysis
Coherence	Several large cohort studies have suggested that excess thyroid hormones is a risk factor for dementia.^13–16 In the most recent cohort study, researchers identified an elevated risk of cognitive disorders as a potential adverse outcome associated with excess thyroid hormones.¹¹	Literature search
Specificity	Pharmacovigilance data indicate a more pronounced association of ETHs with dementia compared to other drugs.	Disproportionality and co-medication analysis
Temporal relationship	The median latency to develop dementia symptoms with ETH therapy was 7.5 days. The median duration of treatment for these cases was 40.5 days. Dementia symptoms were reported during treatment with ETHs.	Time-to-onset analysis
Reversibility	This criterion has limited value because of insufficient data on rechallenge and de-challenge in the FAERS database.	Descriptive

Discussion

In this study, we conducted a comprehensive analysis comprising 4 key objectives. First, we characterized the clinical features of dementia symptoms related to ETH therapy by analyzing postmarketing data from the FAERS database. Second, we determined the disproportional reporting signals regarding ETH therapy and dementia symptoms. Third, we analyzed the dose and TTO for these cases, and finally, based on the results of this study and existing literature, we summarized the relevant evidence demonstrating a potential association between ETH therapy and dementia symptoms.

Exogenous thyroid hormones in the body manifest as heart palpitations, trembling limbs, orthopnea, weight loss, and sleep disturbance, which are similar to the distribution of ETH-associated ADRs across life systems.³⁷ The results revealed that dementia symptoms were one of the most common ADRs. In addition, dementia accounted for a largely constant proportion of all ADRs each year (3.4%-6.3%). This stability suggests the importance of ETH-associated dementia symptoms and indicates a potential relationship. We then compared the clinical characteristics of patients treated with ETHs and dementia symptoms. Based on the available data on adverse events, dementia symptoms were significantly more common in females and adults. These sex disparities and age distributions are also evident in epidemiological investigations of thyroid diseases, which have demonstrated a higher percentage of ETH treatment among females and middle-aged and elderly people.^38,39 Furthermore, 59 680 cases involving ETHs were reported between 2004 and 2023, with the proportions of females, males, and unknown sex being 76.60%, 12.61%, and 10.79%, respectively. The proportions of children, adults, older individuals, and those of unknown age were 1.56%, 34.72%, 19.76%, and 43.93%, respectively. Therefore, the higher reporting by females and adults may also be related to the distribution of reports. By analyzing these data patterns and trends, this study provides preliminary insights into the potential association between ETH therapy and dementia symptoms.

We then performed the DPA of ETHs against all other drugs in the FAERS database using the same methodology used in previous pharmacovigilance studies.^28,40 These results indicated the presence of ETH-associated dementia symptom signals. Hypothyroidism is an indication in a large proportion of the included population and may lead to cognitive dysfunction.⁴¹ To reduce the influence of disease factors in the cases themselves on DPA results, we performed sensitivity analyses. Specifically, we restricted the control population from all databases to the geriatric population, the population with Parkinson-like events, the population with central nervous system vascular disorders, and the population with hyperglycemia/new-onset diabetes mellitus (previous studies have noted a higher likelihood of dementia in these specific physiological or pathological state populations) to counteract false positive signals of potential disease-induced dementia symptoms.^34,35 In addition, subgroup analyses were performed, considering the possible masking and competing effects of reporter type, sex, age, and indications. After restricting cases according to the screening conditions, the results remained positive in all subgroups. Validation of the above analysis further confirmed the association between ETH therapy and dementia symptoms.

TTO analyses showed that the median TTO of dementia symptoms was 7.5 days after the use of ETHs. Dementia symptoms are not life-threatening and are more likely to manifest as a mild decrease in quality of life; therefore, treatment is not terminated. The median duration of ETH treatment was 40.5 days. Analyses of whether mild manifestations of dementia symptoms progress to severe cognitive impairment could not be performed because of the lack of validated time–disease progression data. Controversy remains as to whether a dose-dependent relationship exists between ETH therapy and dementia symptoms.¹¹ In this study, statistically significant differences were observed between the total dose and the dose based on body weight between the dementia and nondementia symptom groups. However, this difference was subtle because of the large number of cases included in the study and was not clinically significant. Therefore, we did not find any evidence to support the existence of a dose-dependent relationship. Notably, the doses in cases with dementia symptoms were in accordance with the labels. This suggests that even routine therapeutic doses of ETHs may cause the development of dementia symptoms, whereas previous studies have suggested that only large amounts of thyroid hormones in vivo may be a risk factor for dementia.¹¹ Moreover, given that oral administration is a common mode of administration for ETHs, absorption may decrease with age because absorption from the gastrointestinal tract ranges from 40% to 80%.³⁶ Therefore, more in-depth pharmacological and pharmacokinetic studies are required to further investigate the dose-exposure-response potential.

Based on the above results and assessments of available research, we adopted the adjusted Bradford Hill Criteria from previous publications and assessed the point-by-point link between ETH therapy and dementia symptoms. Several large cohort studies have suggested that excessive thyroid hormone levels are a risk factor for dementia.^13-16 In a recent cohort study, researchers highlighted that an elevated risk of cognitive disorders is a potential adverse outcome associated with excessive thyroid hormone levels.¹¹ In addition, increased thyroid hormone levels promote rapid metabolism and trigger oxidative stress, affecting the viability of neurons in patients, which may lead to dementia.^42,43 Some studies have shown an association between dementia and excess levels of T3 and T4, as well as elevated levels of T4 in patients with mild dementia.⁴⁴ Through a comprehensive retrospective analysis of the strength of association, analogy, and consistency metrics of ETHs and dementia, we concluded that the evidence suggests an association between ETH therapy and dementia. Cohort studies, case reports, and FAERS database cases all highlight the need to consider that ETH therapy may be associated with dementia symptoms and that this association can broadly affect the thyroid disease population. In particular, more thought should be given to the need to initiate or maintain the use of ETHs in patients with subclinical disease. In addition, given that replacement therapy for patients with hypothyroidism requires the long-term use of ETHs, individualized dosing regimens should be considered to reduce the incidence of potential ADRs and retain maximum benefits. Clinicians should recognize that the use of ETHs in patients requires vigilance, thorough monitoring, and specialized counseling to enhance their quality of life.

Nevertheless, our study had some limitations. First, as a spontaneous reporting system, the FAERS has inherent shortcomings, such as duplicate records with variable information quality. Despite manual corrections and deletions, a few duplicate cases may exist.^45,46 Second, because of the limited availability of dose and TTO data, the number of valid cases may have been inadequate. Consequently, the conclusions drawn from dose and TTO analyses should be regarded as low-quality evidence. Finally, the DPA method only involves signal mining and does not necessarily represent true causality; thus, higher-quality and larger prospective trials are required to validate the findings of this study.

Conclusion and Relevance

In this study, we explored the relationship between ETH therapy and dementia symptoms using DPA. The results suggest an association between ETH therapy and dementia symptoms based on clinical characteristics, disproportionality, dose, and TTO analysis. As such, clinicians should pay closer attention to patients with thyroid disease, and perform more comprehensive monitoring to carefully consider their susceptibility to dementia symptoms. The results of this study enhance our current understanding of ETH-associated ADRs, which is important for maintaining the quality of life of patients and providing strong support for clinical medication decisions.

Supplemental Material

sj-docx-1-aop-10.1177_10600280241252211 – Supplemental material for Exploring the Link Between Exogenous Thyroid Hormones and Dementia Symptoms: A Real-World Disproportionality Analysis of FDA Adverse Event Reporting System

Supplemental material, sj-docx-1-aop-10.1177_10600280241252211 for Exploring the Link Between Exogenous Thyroid Hormones and Dementia Symptoms: A Real-World Disproportionality Analysis of FDA Adverse Event Reporting System by Jianxing Zhou, Weipeng Lai, Zipeng Wei, Baohua Xu, Maobai Liu, Nanwen Zhang and Xuemei Wu in Annals of Pharmacotherapy

Footnotes

Acknowledgements

Thanks to the U.S. Food and Drug Administration for providing a free source of data for the study.

Authors’ Note

Prior Presentation: This manuscript has not been published or presented elsewhere in part or in entirety and is not under consideration by another journal.

Availability of Data and Materials

The datasets generated and/or analyzed during this study is available in the U.S. FAERS database (). The code generated and/or analyzed in this study is available from the corresponding author on reasonable request.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Ethics Approval and Consent to Participate

Ethical approval was not required as the study was conducted using de-identified publicly available data.

Consent for Publication

Not applicable.

ORCID iD

Xuemei Wu

Supplemental Material

Supplemental material for this article is available online.

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