key: cord-1037785-61m28tc7 authors: Unalp-Arida, A.; Ruhl, C. E. title: Prepandemic prevalence estimates of fatty liver disease and fibrosis defined by liver elastography in the United States date: 2022-04-06 journal: nan DOI: 10.1101/2022.04.05.22273458 sha: 4072e1592adf273c4f07221acf7cade30d9aa369 doc_id: 1037785 cord_uid: 61m28tc7 Background & Aims. Fatty liver disease is a growing public health burden with serious consequences. We estimated prepandemic prevalence of fatty liver disease determined by transient elastography assessed hepatic steatosis and fibrosis, and examined associations with lifestyle and other factors in a United States population sample. Methods. Liver stiffness and controlled attenuation parameter (CAP) were assessed on 7,923 non-Hispanic white, non-Hispanic black, non-Hispanic Asian, and Hispanic men and women aged 20 years and over in the National Health and Nutrition Examination Survey (NHANES) 2017-March 2020 prepandemic data. Results. The prevalence of fatty liver disease estimated by CAP >300 dB/m was 28.8% and of fibrosis (liver stiffness >8 kPa) was 10.4%. Only 7.2% of participants with fatty liver disease and 10.9% with fibrosis reported being told by a health care provider that they had liver disease. In addition to known risk factors such as metabolic factors and ALT, persons with fatty liver disease were less likely to meet physical activity guidelines, more likely to be sedentary for 12 or more hours a day, and reported a less healthy diet. Persons with fibrosis were less likely to have a college degree and reported a less healthy diet. Conclusion. In the U.S. population, most persons with fatty liver disease are unaware of their condition. Although physical activity and dietary modifications might reduce the fatty liver disease burden, the COVID pandemic has been less favorable for lifestyle changes. There is an urgent need for fatty liver disease management in high-risk individuals using transient elastography or other noninvasive methods to intervene in disease progression. Key words: Controlled attenuation parameter; liver stiffness; nonalcoholic fatty liver disease; National Health and Nutrition Examination Survey. NHANES 2017-2018 which provided the first U.S. representative transient elastography liver stiffness and CAP observations. 20 Using those data, we reported transient elastography-derived hepatic steatosis and fibrosis distributions in U.S. adults and their associations with body composition. 21 That analysis was limited by the smaller sample size with available transient elastography data using a single 2-year survey cycle. Additional liver elastography data recently became available with the release of the NHANES 2017-March 2020 prepandemic data enabling increased precision of prevalence estimates and ability to detect differences among population groups to further explain liver disease heterogeneity. In the current report, we estimated prepandemic prevalence of fatty liver disease determined by transient elastography assessed hepatic steatosis and fibrosis, and of NAFLD and MAFLD in a United States population sample. We also examined fatty liver disease associations, including those with lifestyle factors not available at the time of our previous analysis, to investigate the potential impact of adverse social factors. The NHANES is conducted in the United States by the National Center for Health Statistics (NCHS) of the Centers for Disease Control and Prevention (CDC). 22 The survey consists of interview, examination, and laboratory data collected from a complex multistage, stratified, clustered probability sample representative of the civilian, noninstitutionalized population with oversampling of non-Hispanic blacks, Hispanics, Asians, low income persons, and older adults. The CDC ethics review board approved the survey, and all participants provided written informed consent. The current analysis utilized data collected from 2017 through March 2020 for use under a CC0 license. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 6, 2022. ; https://doi.org/10.1101/2022.04.05.22273458 doi: medRxiv preprint when the CDC NCHS stopped the survey due to the emerging COVID-19 pandemic, during which transient elastography was used to measure hepatic steatosis and fibrosis. Vibration controlled transient elastography using FibroScan ® 502 V2 Touch (Echosens TM North America, Waltham, MA) was performed on eligible NHANES 2017-March 2020 participants. 20 Multiple measurements up to ≥ 30 were made on each participant using a medium (M; 72% of participants) or large (XL) probe. Hepatic fibrosis was measured using transient elastographyderived liver stiffness in kilopascals (kPa) with median, interquartile range (IQR), and IQR/median calculated for each participant. Simultaneously, hepatic steatosis was measured using CAP in decibels per meter (dB/m) with median and IQR calculated for each participant. Age (years), sex, race-ethnicity (non-Hispanic white, non-Hispanic black, non-Hispanic Asian, Hispanic, or other), education (less than high school graduate, high school graduate or GED or equivalent, some college or associate degree, college graduate or above), income, diagnosed diabetes, blood pressure medication use, liver disease history, cigarette smoking (never, former, current), alcohol use, health insurance coverage (private, public only, or uninsured), physical activity, and healthiness of diet (excellent/very good, good, or fair/poor) were ascertained by interview. Income was measured by the poverty income ratio (ratio of family income to poverty threshold) and categorized as quartiles. Current alcohol use was categorized as none, moderate (>0-<3 drinks/day for men or >0-<2 drink/day for women), or heavy (≥3 drinks/day for men or ≥ 2 drink/day for women). Whether or not the participant met WHO physical activity guidelines and sedentary activity (hours per day) were determined from responses to the Global Physical Activity Questionnaire. 23 A person was considered to have met the guidelines if they did at least for use under a CC0 license. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 6, 2022. ; https://doi.org/10.1101/2022.04.05.22273458 doi: medRxiv preprint 150-300 minutes of moderate-intensity aerobic physical activity, or at least 75-150 minutes of vigorous-intensity aerobic physical activity, or an equivalent combination of moderate-and vigorous-intensity activity per week. Body measurements including standing height (cm), weight (kg), waist circumference (cm), and hip circumference (cm) were ascertained during the mobile examination center visit, and body mass index (BMI; weight [kg]/height [m 2 ]) and waist-to-hip circumference ratio were calculated. Systolic and diastolic blood pressure (mmHg) were measured. Serum was tested for hemoglobin A 1C (%), total and high-density lipoprotein (HDL) cholesterol (mg/dL), alanine aminotransferase (ALT, IU/L), aspartate aminotransferase (AST, IU/L), gamma-glutamyltransferase (GGT, IU/L), and high-sensitivity C-reactive protein (mg/L). Among participants examined in the morning after an overnight fast of 8 to less than 24 hours, serum was also tested for triglycerides (mg/dL), glucose (mg/dL), and insulin (pmol/L). Pre-diabetes was defined as hemoglobin A 1C were excluded (n=333). Participants who did not undergo liver elastography (refused, insufficient time, physical or technical limitations) or had no complete stiffness measures were also excluded (n=288). The resulting liver elastography analysis sample consisted of 7,923 persons (Supplemental Figure 1 ). Of these, 7,396 (93.6%) had complete liver elastography and 527 were considered by the NCHS to have a partial examination because of fasting < 3 hours (n=248), 1 to <10 valid measures obtained (n=99), or a stiffness IQR/median ≥ 30% (n=180) (Supplemental Table 1 ). Higher BMI, stiffness, and CAP of participants in the latter two groups suggested they had potentially more severe liver injury; consequently, as in our previous NHANES 2017-2018 analysis we included them in our current analysis to reflect the full range of U.S. representative population liver disease. 21 Analyses including fasting laboratory measures were conducted among morning examined fasted participants (n=3,576). for use under a CC0 license. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. We evaluated characteristics of participants with complete and partial liver elastography by comparing continuous factor means (standard deviations (SD)) using analysis of variance and categorical factor percentages using chi-square (χ 2 ) tests or linear regression. Unadjusted relationships of fatty liver disease and fibrosis with demographic, clinical, lifestyle, and social characteristics were examined by comparing continuous factor means (SD) using t-tests and categorical factor percentages using chi-square (χ 2 ) tests. Age-adjusted relationships were explored using logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI). Multiple logistic regression analysis was used to determine relationships of fatty liver disease and fibrosis with participant characteristics after adjustment for all other factors in the model. Age, sex, and race-ethnicity were retained in models. A biological plausibility approach was followed to test anthropometric measures (BMI, BMI and waist-to-hip ratio, and waist circumference), metabolic factors (diabetes, total and HDL cholesterol, elevated blood pressure, C-reactive protein, and CAP (for liver stiffness models)), liver enzymes (ALT, AST, and GGT), lifestyle factors (alcohol use, smoking, physical activity, and diet), and social factors (education, income, and health insurance coverage) for inclusion in models. 28 For factors that were highly correlated, the measure that explained the greatest variance (R 2 ) was selected. Factors were retained in final models if p<0.10. Factors that were not normally distributed were expressed as deciles (10 th percentiles) for regression analyses using cut points shown in Supplemental Table 2 . P-values were two-sided, and P<0.05 indicated statistical significance. Sample weights accounted for unequal selection probabilities and nonresponse. Variance calculations accounted for survey design effects using Taylor series linearization. 29 SAS 9.4 (SAS Institute, Cary, NC) and SUDAAN 11 (RTI, Research Triangle Park, NC) were used. for use under a CC0 license. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 6, 2022. ; https://doi.org/10.1101/2022.04.05.22273458 doi: medRxiv preprint Among 7,923 adult participants with liver elastography measures, mean (SD) CAP was 264.6 (63.1) dB/m and mean liver stiffness was 5.9 (4.9) kPa ( Table 1) . The overall prevalence of fatty liver disease (CAP >300 dB/m) was 28.8% (95% C.I., 27.1%-30.6%). The prevalence of fibrosis risk (liver stiffness >8 kPa) was 10.4% (95% C.I., 8.8%-12.2%) in the overall population and as high as 22.8% (95% C.I., 19.2%-26.8%) among persons with fatty liver disease. The NAFLD definition (CAP >300 dB/m without heavy alcohol use) was met by 26.4% (95% C.I., 24 .7%-28.2%) of participants, while 1.3% had elevated CAP with heavy alcohol use and 1.1% had elevated CAP and missing alcohol use data so NAFLD status could not be determined. The MAFLD definition (CAP >300 dB/m and fulfilled metabolic criteria) was met by 28.3% (95% C.I., 26.6%-30.1%) of participants, while 0.4% had elevated CAP, but did not fulfill metabolic criteria and 0.1% had elevated CAP, but MAFLD status could not be determined due to incomplete metabolic data. Prevalence of fibrosis did not differ between persons with NAFLD (22.9%; 95% C.I., 19.2%-27.0%) and MAFLD (22.9%; 95% C.I., 19.3%-27.1%). Health care provider diagnosed liver disease ever was reported by 4.6% of all participants and a current liver disease diagnosis by 2.6%. The mean (SD) duration of liver disease was 11.0 (12. 3) years. The prevalence was 2.3% for fatty liver (in contrast to transient elastography assessed 28 .8%), 0.1% for liver fibrosis (in contrast to transient elastography assessed 10.4%), 0.3% for liver cirrhosis, 0.8% for viral hepatitis, 0.2% for autoimmune hepatitis, and 1.2% for other liver disease. Men had a higher prevalence of transient elastography identified fatty liver disease, fibrosis risk, NAFLD, and MAFLD compared with women (Table 1 ). Sex differences in other participant characteristics were similar to those reported previously among the NHANES 2017-2018 sample. 21 In addition, while women less often met physical activity guidelines, they were for use under a CC0 license. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 6, 2022. ; https://doi.org/10.1101/2022.04.05.22273458 doi: medRxiv preprint also less likely to spend 12 or more hours per day in sedentary behavior. Among the fasting sample, men had higher triglyceride and glucose levels. Participants with fatty liver disease were more likely to be Hispanic and less likely to be non-Hispanic black or non-Hispanic Asian ( Table 2) . This was consistent among both men and women (Figure 1 ). Among men, fatty liver disease prevalence was higher among non-Hispanic Asians compared with non-Hispanic blacks; whereas, among women non-Hispanics blacks and non-Hispanic Asians did not differ significantly. Among persons with fatty liver disease, only 7.2% reported ever having been told by a health care provider that they had liver disease and only 4.3% reported still having liver disease. Persons with fatty liver disease were older and more likely to have metabolic risk factors, higher liver enzymes, and to be former smokers. They were less likely to meet physical activity guidelines, more likely to be sedentary for 12 or more hours a day, and self-reported a less healthy diet (Table 2, Figure 2A ). Fatty liver disease prevalence was highest among persons who did not meet physical activity guidelines and were sedentary for 12 or more hours a day ( Figure 2B ). The higher fatty liver disease prevalence among persons with less favorable lifestyle habits was seen across sex and race-ethnicity groups, although differences did not reach statistical significance among all groups (Supplemental Participants with fatty liver disease were less likely to have a college degree, but did not differ with regard to income (Table 2, Supplemental Figure 7 ). The lower fatty liver disease prevalence among persons with the highest education level was seen across sex and raceethnicity groups, although differences did not reach statistical significance among all groups (Supplemental Figures 8-11) . ALT, AST, and GGT were elevated among only 22.7%, 10.7%, and 22.5% of persons with fatty liver disease, respectively (Table 2) . for use under a CC0 license. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 6, 2022. With adjustment for age, non-Hispanic Asian race-ethnicity was no longer inversely associated with fatty liver disease ( Table 3 ). An association appeared with the lowest income quartile, while other relationships were similar. In multivariate-adjusted analysis, fatty liver disease was positively associated with non-Hispanic Asian race-ethnicity ( Table 4 ). Associations remained with older age, prediabetes and diabetes, higher BMI, waist-to-hip ratio, total cholesterol, blood pressure, C-reactive protein, and ALT and inversely with non-Hispanic black race-ethnicity and HDL cholesterol. There was a trend toward an association with less physical activity, more sedentary behavior, and a less healthy diet (0.05300 dB/m was high (28.8%) and requires scalable management approaches at a population level. [5] [6] The prevalence of fibrosis, defined as liver stiffness >8 kPa, was also high overall (10.4%), especially among persons with fatty liver disease (22.8%). Fatty liver disease prevalence estimates ranged from 35.1% using a cut point of 285 dB/m, to 47.8% with a cut point of 263 dB/m, to over half of the U.S. population (56.7%) using a cut point of 248 dB/m in analyses of NHANES 2017-2018. [18] [19] Prevalence of hepatic steatosis and fibrosis was even higher among some U.S. population groups, such as persons with type 2 diabetes mellitus. 30 The fibrosis prevalence estimated in the general U.S. population was higher compared with a Dutch population study that used the same liver stiffness cut point of 8.0 kPa (10.4% vs. 6.0%), despite the older age of the Dutch population sample (45 years and over). 9 Among European population-based studies using transient elastography for screening with cut points ranging from 7.9 kPa to 9.6 kPa, fibrosis prevalence varied from 2.4% to 7.5%. [31] [32] [33] [34] [35] [36] Among Asian population studies with cut points ranging from 5.9 kPa to 9.6 kPa, fibrosis prevalence varied from 2.0% to 14.3%. 31 This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 6, 2022. ; https://doi.org/10.1101/2022.04.05.22273458 doi: medRxiv preprint resonance spectroscopy found a similar prevalence of MAFLD and NAFLD (25.9% vs. 25.7%), but reported a lower incidence of MAFLD compared with NAFLD, especially among persons with low BMI. 10 A Dutch population-based study found MAFLD and NAFLD prevalence of 34.3% and 29.8%, respectively, using ultrasound and persons with MAFLD only, but not those with NAFLD only, were more likely to have fibrosis. 9 MAFLD was found to be more strongly associated with all-cause mortality compared with NAFLD in the U.S. population. 40 However, additional longitudinal studies of the long-term effects of the proposed definition will be needed. The extent of undiagnosed liver disease in the U.S. population is striking and requires a unified public health response including risk stratification by primary care providers. 5 Among persons with fatty liver disease, only 7% reported ever having been told by a health care provider that they had liver disease and among persons with more severe disease represented by fibrosis, only a minimally higher proportion, 11%, reported ever having been told they had liver disease. Liver disease awareness has improved little from previous reports in the U.S. population using earlier NHANES data in which NAFLD was identified by liver fat scores. 41 Fatty liver disease may remain asymptomatic and not come to expert medical attention until reaching an advanced stage. However, despite the current lack of an approved pharmacologic therapy, persons identified early with fatty liver disease can benefit from recommendations for diet and exercise for weight loss, as well as treatment of cardiovascular disease risk factors. The low liver disease awareness that we report indicates that even among high-risk groups, many persons are not being evaluated for fatty liver disease despite the availability of noninvasive screening techniques such as transient elastography and liver fat and fibrosis scores. Routine screening for NAFLD in highrisk groups attending primary care, diabetes, or obesity clinics is not currently recommended by for use under a CC0 license. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 6, 2022. ; https://doi.org/10.1101/2022.04.05.22273458 doi: medRxiv preprint the American Association for the Study of Liver Diseases. 27 However, these are often the health care settings in which patients at high risk for fatty liver disease are first seen. Currently, there is insufficient awareness of the growing NAFLD burden among both the public and the health care providers caring for them. A recent global survey of physicians' knowledge about NAFLD found a significant knowledge gap for the identification, diagnosis, and management of NAFLD, especially among primary care providers who are often the first to see patients at risk for NAFLD. 42 To address this challenge, a Clinical Care Pathway has recently been developed by the American Gastroenterological Association to provide guidance on the screening, diagnosis, and treatment of NAFLD. 6 We found associations with known fatty liver disease risk factors, including age, non-Hispanic Asian race-ethnicity, BMI, waist-to-hip ratio, pre-diabetes and diabetes, total cholesterol, blood pressure, C-reactive protein and ALT, and inverse relationships with non-Hispanic black raceethnicity and HDL cholesterol. Fibrosis was associated with BMI, diabetes, blood pressure, AST, CAP, and total cholesterol (inverse). Lower cholesterol among persons with fibrosis was previously reported using earlier NHANES data. 13, 43 In the current analysis we also examined lifestyle factors and found that persons with fatty liver disease were less likely to meet physical activity guidelines, more likely to be sedentary for 12 or more hours a day, and self-reported a less healthy diet. Fatty liver disease prevalence was highest among persons with both a lower level of physically activity and a higher level of sedentary behavior. Associations with physical activity, sedentary behavior, and diet were only partially explained after accounting for demographic, clinical, and other lifestyle factors. Similar associations were seen for fibrosis, though relationships with physical activity and sedentary behavior did not remain after for use under a CC0 license. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 6, 2022. ; https://doi.org/10.1101/2022.04.05.22273458 doi: medRxiv preprint accounting for other factors, possibly due to heterogeneity and smaller numbers of persons with fibrosis compared with fatty liver disease. Further analysis of persons who fasted revealed a stronger association of sedentary behavior with fatty liver disease and fibrosis suggesting that accounting for triglycerides and/or insulin may have augmented this relationship similar to an earlier CDC report that sedentary behavior was associated with higher insulin levels in the U.S. population. 44 The higher fatty liver disease and fibrosis prevalence among persons with detrimental lifestyle habits was seen across sex and race-ethnicity groups, although differences did not reach statistical significance among all groups due to heterogeneity and smaller sample sizes. These findings suggest that adoption of beneficial physical activity and dietary habits could have broad impact across U.S. population groups on the fatty liver disease burden. Beneficial effects of a healthier lifestyle on fatty liver disease and fibrosis were also reported in previous papers using NHANES 2017-2018 data. 12-14 Despite the potential benefit of lifestyle interventions across demographic groups, the COVID-19 pandemic has had a detrimental effect on lifestyle habits of less advantaged groups. A recent systematic review found decreased physical activity levels during the COVID-19 lockdown across almost all reviewed populations and increased sedentary behavior in the majority of studies included. 45 If these trends continue, they could exacerbate the growing burden of fatty liver disease and fibrosis in the U.S. We examined the relationship of socioeconomic status with fatty liver disease and fibrosis using educational attainment and poverty income ratio (ratio of family income to poverty threshold). As an example of poverty income ratio, the poverty threshold was $26,200 for a family of 4 in 2020. 46 Therefore, a family of 4 with a total income of $26,200 would have a poverty income for use under a CC0 license. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 6, 2022. However, we found a strong association between a self-reported less healthy diet and higher prevalence of fatty liver disease and fibrosis. These relationships should be explored further when 24-hour dietary recall data become available. Similarly, we were unable to evaluate the relationship of viral hepatitis with CAP and liver stiffness or to exclude participants with viral hepatitis in identifying NAFLD due to the lack of data on viral hepatitis B and C serum markers This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 6, 2022. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 6, 2022. ; https://doi.org/10.1101/2022.04.05.22273458 doi: medRxiv preprint ≥ 3 drinks/day for men and ≥ 2 drinks/day for women. for use under a CC0 license. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 6, 2022. ; https://doi.org/10.1101/2022.04.05.22273458 doi: medRxiv preprint This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 1 Values are percentage or mean (standard deviation). 2 Percentage total is less than 100% because persons of "other" race-ethnicity are not shown. 3 ALT >40 IU/L in men or >31 IU/L in women. 4 AST >37 IU/L in men or >31 IU/L in women. 5 GGT >51 IU/L in men or >33 IU/L in women. 6 Moderate alcohol use was <3 drinks/day for men and <2 drinks/day for women; heavy alcohol use was ≥ 3 drinks/day for men and ≥ 2 drinks/day for women. 7 Does not meet physical activity guidelines. Compared to fatty liver disease or fibrosis risk: a p<0.001, b p<0.05. for use under a CC0 license. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 1 Does not meet physical activity guidelines. for use under a CC0 license. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 6, 2022. for use under a CC0 license. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 6, 2022. ; https://doi.org/10.1101/2022.04.05.22273458 doi: medRxiv preprint This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 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