Thyroid Circadian and Circannual Rhythms in Thyroid Hormones: Determining the TSH and Free T4 Reference Intervals Based Upon Time of Day, Age, and Sex. (doi: 10.1089/thy.2014.0589) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.

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Circadian and Circannual Rhythms in Thyroid Hormones:   Determining the TSH and Free T4 Reference Intervals Based Upon Time of Day, Age, and Sex. Joel Ehrenkranz MD1, Phillip R. Bach Ph.D.2, Gregory L. Snow Ph.D3., Alison Schneider MD4, Jo Lynn Lee M.S.5, Sarah Ilstrup MD6, Sterling T. Bennett MD7, Salvatore Benvenga MD8

1. Dept. of Medicine, Intermountain Medical Center, 5121 South Cottonwood Street, Murray, UT 84107. [email protected]. 801-503-6332. 2. Intermountain Central Laboratory, 5121 South Cottonwood Street, Murray, UT 84107. [email protected]. 801-662-2180 3. Intermountain Healthcare Research, Statistical Data Center, 8th Ave & C Street, Salt Lake City, UT 84143. [email protected] 801-408-8111 4. Dept. of Medicine, McKee-Dee Hospital, 4401 Harrison Boulevard, Ogden, UT 84403. [email protected]. 801-387-7900 5. Intermountain Healthcare, 36 So. State Street, Salt Lake City, UT 84111-1486. [email protected]. 801-507-8068 6. Intermountain Central Laboratory, 5121 South Cottonwood Street, Murray, UT 84107. [email protected]. 801.507.2146 7. Intermountain Central Laboratory, 5121 South Cottonwood Street, Murray, UT 84107. [email protected]. 801-507-2135 8. Dept. of Medicine, Policlinico Universitario di Messina, Via Consolare Pompea, 1, Messina, Italy. [email protected]. +39 090 221 710

Running Title: Circadian and Circannual Variation in Thyroid Hormones Key Words: TSH, free T4, circadian, seasonal, reference interval

 

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Thyroid Circadian and Circannual Rhythms in Thyroid Hormones: Determining the TSH and Free T4 Reference Intervals Based Upon Time of Day, Age, and Sex. (doi: 10.1089/thy.2014.0589) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.

Version 4.3 May 2, 2015

 

Abstract

Background: Establishing the reference interval for TSH and free T4 is clinically important because a number of disease states have been linked to alterations in TSH and free T4 concentrations that are within the 95% confidence interval for normal thyroid hormone values. Age, sex, time of day, and ethnicity are known to affect circulating levels of TSH and free T4, but have not been used to establish reference intervals. The purpose of this study was to define the reference interval for TSH and free T4 taking into account age, sex, ethnicity, and circadian and circannual variability. Methods: We performed a retrospective analysis of 465,593 TSH and 112,994 free T4 measurements from subjects ages 1-104 with no thyroid disease using a single TSH and free T4 immunoassay method. Boundaries for the central 95% of patient values, taking into account hour of day, day of year, sex, and age were calculated. Results: Females had significantly higher TSH and free T4 levels than males; the magnitude of these differences did not exceed 0.1 mIU/L or 0.1 ng/dl respectively. Although the 2.5% TSH reference interval remains constant through the day, date, and age ranges, the upper limit (97.5 %) of the TSH reference interval increases from 6.45 to 7.55 mIU/L with age, due primarily to a progressive increase in the amplitude of the nocturnal TSH surge. Additionally, significant ethnic differences in TSH circadian periodicity occur between Afro-American, Pacific Island, and Caucasian populations. Conclusions: The reference interval for TSH varies significantly by age, sex, hour of day, and ethnicity. Time of year does not affect the TSH reference interval, and age, sex, hour of day and time of year do not affect the free T4 reference interval.

 

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Thyroid Circadian and Circannual Rhythms in Thyroid Hormones: Determining the TSH and Free T4 Reference Intervals Based Upon Time of Day, Age, and Sex. (doi: 10.1089/thy.2014.0589) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.

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Introduction

In iodine-sufficient populations, the reference range for serum TSH in adults ages 20-59 is 0.45-4.5 mIU/L. (1,2,3). Defining the upper and lower limit of normal TSH concentration is clinically significant because many studies show that the difference between an individual’s TSH value and the reference interval mean correlates with clinical pathology (4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 16, 17). Age (3), sex, ethnicity, iodine intake (18), body mass index (19), reproductive status (20) and TSH assay method are recognized as independent factors that modify the TSH reference range (4). Serum concentrations of TSH and free T3 are reported to show significant circadian periodicity (21, 22, 23, 24). The circadian variation in TSH is absent in infants younger than one month old (25) and in patients with Sheehan’s syndrome (26). Sleep deprivation (27, 28) and short-term untreated hypothyroidism (29) affect the nocturnal TSH surge. In contrast, the circadian TSH rhythm is not affected by treatment of hypothyroidism with either T4 or T3 (30). In addition to diurnal variations in thyroid hormone levels, circannual changes in a number of aspects of thyroid anatomy, function, and pathology, including thyroid size, TSH, free and total T4 and T3 concentrations, and presentation of thyroid disease vary throughout the year (31, 32, 33, 34, 35, 36, 37, 38, 39, 40). Reference ranges for thyroid hormone values, however, do not take into account temporal that is circadian or circannual, variations in thyroid hormone concentrations that are circadian or circannual. To investigate whether diurnal or seasonal fluctuations in thyroid hormone values represent a significant independent source of reference interval variability, we conducted a retrospective review of the diurnal and annual variation in TSH and free T4 levels in 465,593 outpatients with no known thyroid disease. MATERIALS AND METHODS This study, approved by the Intermountain Healthcare (Salt Lake City, Utah) Institutional Review Board, used data collected between June, 2010 and November, 2013 extracted from the Intermountain Healthcare Enterprise Data Warehouse. Subjects We studied 465,593 TSH measurements from 324,750 outpatients, ages 1-104, identified as having no clinical thyroid disease using the following criteria: • Serum 0.4 < TSH < 10.0 • No diagnosis of thyroid disease • No filled prescription for medications used to treat hyper- or hypothyroidism (supplementary Table 1) • No prescription for lithium, amiodarone, or anti-epileptic medications, • No obstetric event (i.e. miscarriage or delivery) within 9 months of thyroid hormone measurement • No diagnosis of thyroid malignancy. • No hospital admission within 24 hours of blood collection.

 

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Thyroid Circadian and Circannual Rhythms in Thyroid Hormones: Determining the TSH and Free T4 Reference Intervals Based Upon Time of Day, Age, and Sex. (doi: 10.1089/thy.2014.0589) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.

Version 4.3 May 2, 2015

The age, sex, number of TSH determinations   (some patients had TSH measured on more than one occasion) and self-described ethnic distribution of these subjects are shown in Tables 1A and 1B. Outpatient blood testing took place at clinics, outpatient surgery centers, and laboratory drawing facilities located in urban and rural Utah and southern Idaho. Date and time at which each specimen was collected was recorded for each subject. Hormone Assays Serum TSH and free T4 were measured using Abbott Architect immunoassays with external controls performed daily. Data Analysis Quantile regression was used with periodic splines to calculate boundaries for the central 95% of patients given the hour of the day, day of the year, sex, and age group (the 2.5th percentile and 97.5th percentile were computed). Significance of the periodic splines was determined by comparing the smallest p-value, after adjusting for multiple comparisons by using the false discovery rate method within a group of splines, to the alpha level of 0.05. (41, 42, 43) RESULTS Table 2 and Figure 1 display the circadian reference interval (defined as the distribution of values that encompass 95% of all observations) for TSH by sex, age, and time of day. Supplementary Table 2 displays all age band reference intervals differed (p < .05) from the reference interval for individuals of both sexes over 80 years of age. Additionally, for each age band, the reference interval for females was significantly higher than the reference interval for males. Circannual TSH reference intervals are shown in Table 3 and Figure 2. The circannual variation in TSH showed that the upper limit of the 95% reference interval for both sexes and all age groups had a low value of 4.31 in August and peak value of 6.06 in December. The lower limit of the 95% reference interval for TSH was 0.5 throughout the year. Although statistically significant differences in the upper limit of the monthly TSH reference interval were found (p80

Female 27,325 74,288 61,032 31,930 6,637

Total

201,212

Number of Subjects Male 16,244 35,373 41,381 26,017 4,523 123,538

11

Total 43,569 109,661 102,413 57,947 11,160

Number of Observations Female Male Total 33,688 19,077 52,765 101,157 43,912 145,069 95,383 59,933 155,316 53,092 41,537 94,629 10,539 7,275 17,814

324,750

293,859

171,734

465,593

Thyroid Circadian and Circannual Rhythms in Thyroid Hormones: Determining the TSH and Free T4 Reference Intervals Based Upon Time of Day, Age, and Sex. (doi: 10.1089/thy.2014.0589) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.

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Table 1B: Ethnic Distribution

Ethnicity (self-described) Native American (Native American or Alaska Native) Asian Afro-American Pacific Islander NOT Reported Other Unknown Caucasian Total

 

12

N %

1415 4436 2495 2341 28144 15655 15759 254505 324750 0.4% 1.4% 0.8% 0.7% 8.7% 4.8% 4.9% 78.4% 100%

Thyroid Circadian and Circannual Rhythms in Thyroid Hormones: Determining the TSH and Free T4 Reference Intervals Based Upon Time of Day, Age, and Sex. (doi: 10.1089/thy.2014.0589) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.

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Table 2   Circadian TSH (mIU/L) Reference Intervals by Age, Sex, and Time of Day    

1-20

21-40 41-60 61-80 80+  

 

Sex M F M F M F M F M F

Lower limit Median of reference lower interval limit mIU/L) (mIU/L) 0.51-0.73 0.56 0.53-0.72 0.56 0.50-0.63 0.53 0.51-0.64 0.53 0.54-0.65 0.55 0.52-0.61 0.54 0.47-0.66 0.56 0.50-0.66 0.52 0.52-0.74 0.58 0.51-0.57 0.54  

Hour at which nadir of lower limit of reference interval occurs 21:00 19:00 21:00 13:00 18:00 14:00 23:00 20:00 20:00 21:00

Hour at which peak of lower limit of reference Interval peak occurs 07:00 06:00 07:00 06:00 06:00 06:00 07:00 06:00 06:00 08:00

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Upper limit of reference interval 4.37-6.68 4.08-6.51 4.14-5.99 4.12-5.86 4.30-5.94 4.51-6.90 4.59-6.71 4.72-7.58 5.19-6.72 5.26-6.95

Hour at Hour at which nadir which peak of upper of upper Median limit of limit upper reference reference limit interval interval (mIU/L) occurs occurs 5.42 15:00 02:00 5.13 15:00 02:00 4.92 10:00 01:00 4.93 14:00 01:00 5.06 10:00 00:00 5.34 10:00 00:00 5.42 12:00 00:00 5.90 11:00 00:00 6.20 14:00 01:00 6.07 14:00 02:00

Thyroid Circadian and Circannual Rhythms in Thyroid Hormones: Determining the TSH and Free T4 Reference Intervals Based Upon Time of Day, Age, and Sex. (doi: 10.1089/thy.2014.0589) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.

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  Table 3 Circannual TSH (mIU/L) Reference Intervals by Age, Sex, and Time of Day

Age Band (years)

Sex M

1-20 F M 21-40 F M 41-60 F M 61-80 F M 80+ F

 

Jan.

Feb.

March April

May

June

July

Aug.

Sept.

Oct.

Nov.

Dec.

0.574.62 0.544.70 0.554.46 0.524.54 0.574.69 0.544.77 0.575.02 0.545.10 0.616.20 0.586.28

0.584.40 0.554.48 0.574.47 0.544.55 0.564.58 0.534.66 0.584.93 0.555.01 0.595.72 0.565.80

0.594.51 0.564.59 0.564.36 0.534.44 0.584.54 0.554.62 0.584.91 0.554.99 0.605.81 0.575.89

0.564.84 0.534.92 0.584.43 0.554.51 0.594.64 0.564.72 0.595.06 0.565.14 0.575.37 0.545.45

0.584.68 0.554.76 0.574.33 0.544.41 0.574.73 0.544.81 0.584.64 0.554.72 0.555.82 0.525.90

0.584.71 0.554.79 0.554.29 0.524.37 0.584.62 0.554.70 0.574.88 0.544.96 0.595.71 0.565.79

0.584.76 0.554.84 0.564.23 0.534.31 0.574.46 0.544.54 0.584.85 0.554.93 0.575.20 0.545.28

0.574.78 0.544.86 0.554.33 0.524.41 0.584.70 0.554.78 0.574.92 0.545.00 0.555.12 0.525.20

0.594.58 0.564.66 0.564.41 0.534.49 0.584.60 0.554.68 0.594.94 0.565.02 0.645.85 0.615.93

0.584.69 0.554.77 0.564.33 0.534.41 0.594.62 0.564.70 0.604.94 0.575.02 0.585.58 0.555.66

0.594.70 0.564.78 0.554.42 0.524.50 0.574.80 0.544.88 0.625.15 0.595.23 0.625.98 0.596.06

0.574.48 0.544.56 0.574.27 0.544.35 0.604.61 0.574.69 0.604.92 0.575.00 0.565.62 0.535.70

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Thyroid Circadian and Circannual Rhythms in Thyroid Hormones: Determining the TSH and Free T4 Reference Intervals Based Upon Time of Day, Age, and Sex. (doi: 10.1089/thy.2014.0589) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.

Version 4.3 May 2, 2015

 

Table 4 FT4: Number of Subjects and Observations by Age and Sex FT4 Age (years) 1-20 21-40 41-60 61-80 >80   Total

 

Number of Subjects Female Male 8,937 5,478 16,043 5,738 13,715 6,591 6,578 4,212 1,185 746 46,458 22,765

15

Total 14,415 21,781 20,306 10,790 1,931 69,223

Number of Observations Female Male Total 11,560 6,784 18,344 26,268 7,959 34,227 25,765 10,798 36,563 12,800 7,539 20,339 2,160 1,361 3,521 78,553 34,441 112,994

Thyroid Circadian and Circannual Rhythms in Thyroid Hormones: Determining the TSH and Free T4 Reference Intervals Based Upon Time of Day, Age, and Sex. (doi: 10.1089/thy.2014.0589) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.

Version 4.3 May 2, 2015

  Table 5 Circadian Variation of free T4 Reference Interval by Age and Sex

Age Band

1-20

21-40

41-60

61-80

80+

Sex

Lower limit of reference interval (ng/dl) 1

Upper limit of reference interval (ng/dl) 2

M

0.78 - 0.84

1.35 - 1.46

F

0.78 - 0.84

1.34 - 1.44

M

0.76 - 0.82

1.35 - 1.45

F

0.76 - 0.82

1.33 - 1.43

M

0.74 - 0.80

1.37- 1.47

F

0.75 - 0.80

1.35 - 1.45

M

0.75 - 0.81

1.40 - 1.51

F

0.76 - 0.81

1.38 - 1.49

M

0.75 - 0.81

1.46 - 1.56

F

0.75 - 0.81

1.43 - 1.54

1. For all age bands and both genders, the time of day when the lower bound of the reference interval was lowest was 5 AM; the time of day when the lower bound of the reference interval was highest was 10 AM. 2. For all age bands and both genders, the time of day when the upper bound of the reference interval was lowest was midnight; the time of day when the upper bound of the reference interval was highest was 7 AM.

 

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Thyroid Circadian and Circannual Rhythms in Thyroid Hormones: Determining the TSH and Free T4 Reference Intervals Based Upon Time of Day, Age, and Sex. (doi: 10.1089/thy.2014.0589) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.

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Table 6 Circannual Variation of free T4 Reference Interval by Age and Sex

Age band 1-20 21-40 41-60 61-80 80+

Sex female male female male female male female male female male

Lower limit of reference interval (ng/dl) 1 0.80 - 0.82 0.79 - 0.82 0.78 - 0.80 0.77 - 0.79 0.76 - 0.78 0.76- 0.78 0.77- 0.79 0.77 - 0.79 0.77 - 0.79 0.76 - 0.79

Upper limit of reference interval (ng/dl) 2 1.44 - 1.46 1.47 - 1.48 1.43 - 1.45 1.41 - 1.43 1.46 - 1.48 1.44 - 1.46 1.50- 1.52 1.47 - 1.49 1.55 - 1.57 1.52 - 1.54

1. For all age bands and both genders, the month when the lower bound of the reference interval was lowest was February; the month when the lower bound of the reference interval was highest was June. 2. For all age bands and both genders, the month when the upper bound of the reference interval was lowest was September; the month when the upper bound of the reference interval was highest was June

 

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Thyroid Circadian and Circannual Rhythms in Thyroid Hormones: Determining the TSH and Free T4 Reference Intervals Based Upon Time of Day, Age, and Sex. (doi: 10.1089/thy.2014.0589) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.

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Table 7 Composite 24 Hour TSH and free T4 Reference Intervals (2.5%-97.5%) by Age Age (years) 1-20 21-40 41-60 61-80 80+

  TSH (mIU/L) 0.53 - 6.45 0.52 - 6.25 0.53 - 6.55 0.54 - 6.80 0.52 - 7.55 Free T4 (ng/dl) 0.78 - 1.45 0.76 -1.44 0.74 -1.46 0.75 -1.50 0.75 -1.55

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Thyroid Circadian and Circannual Rhythms in Thyroid Hormones: Determining the TSH and Free T4 Reference Intervals Based Upon Time of Day, Age, and Sex. (doi: 10.1089/thy.2014.0589) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.

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Supplementary Table 1 Armour Thyroid (Thyroid (Pork)) 300 mg oral tablet Armour Thyroid (thyroid (pork)) 120 mg oral tablet Armour Thyroid (thyroid (pork)) 15 mg oral tablet Armour Thyroid (thyroid (pork)) 180 mg oral tablet Armour Thyroid (thyroid (pork)) 240 mg oral tablet Armour Thyroid (thyroid (pork)) 30 mg oral tablet Armour Thyroid (thyroid (pork)) 60 mg oral tablet Armour Thyroid (thyroid (pork)) 90 mg oral tablet Cytomel (liothyronine) 25 mcg oral tablet Cytomel (liothyronine) 5 mcg oral tablet Cytomel (liothyronine) 50 mcg oral tablet L-thyroxine/, 40-10 mcg., oral tablet levothyroxine, 1000 mcg, oral tablet levothyroxine sodium, 12.5 mcg, oral levothyroxine sodium, 150 mcg/ml, oral liothyronine HCl, 20 mcg, oral liothyronine sodium, 75 mcg, oral capsule Levothroid (levothyroxine) 100 mcg oral tablet Levothroid (levothyroxine) 112 mcg oral tablet Levothroid (levothyroxine) 125 mcg oral tablet Levothroid (levothyroxine) 137 mcg oral tablet Levothroid (levothyroxine) 150 mcg oral tablet Levothroid (levothyroxine) 175 mcg oral tablet Levothroid (levothyroxine) 200 mcg oral tablet Levothroid (levothyroxine) 25 mcg oral tablet Levothroid (levothyroxine) 300 mcg oral tablet Levothroid (levothyroxine) 50 mcg oral tablet Levothroid (levothyroxine) 75 mcg oral tablet Levothroid (levothyroxine) 88 mcg oral tablet levothyroxine (Bulk) 100 % Powder levothyroxine 100 mcg capsule levothyroxine 112 mcg capsule levothyroxine 125 mcg capsule levothyroxine 13 mcg capsule levothyroxine 137 mcg capsule levothyroxine 150 mcg capsule levothyroxine 200 mcg for injection levothyroxine 25 mcg capsule levothyroxine 50 mcg capsule levothyroxine 500 mcg for injection levothyroxine 75 mcg capsule  

4

Thyroid Circadian and Circannual Rhythms in Thyroid Hormones: Determining the TSH and Free T4 Reference Intervals Based Upon Time of Day, Age, and Sex. (doi: 10.1089/thy.2014.0589) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.

Version 4.3 May 2, 2015

levothyroxine 88 mcg capsule   levothyroxine Sodium, 100 mcg, tablet, oral levothyroxine Sodium, 112 mcg, tablet, oral levothyroxine Sodium, 125 mcg, tablet, oral levothyroxine Sodium, 137 mcg, tablet, oral levothyroxine Sodium, 150 mcg, tablet, oral levothyroxine Sodium, 175 mcg, tablet, oral levothyroxine Sodium, 200 mcg, tablet, oral levothyroxine Sodium, 200 mcg, vial, Intravenous levothyroxine Sodium, 25 mcg, tablet, oral levothyroxine Sodium, 300 mcg, tablet, oral levothyroxine Sodium, 50 mcg, tablet, oral levothyroxine Sodium, 75 mcg, tablet, oral levothyroxine Sodium, 88 mcg, tablet, oral Levoxyl (Levothyroxine) 300 mcg oral tablet Levoxyl (levothyroxine) 100 mcg oral tablet Levoxyl (levothyroxine) 112 mcg oral tablet Levoxyl (levothyroxine) 125 mcg oral tablet Levoxyl (levothyroxine) 137 mcg oral tablet Levoxyl (levothyroxine) 150 mcg oral tablet Levoxyl (levothyroxine) 175 mcg oral tablet Levoxyl (levothyroxine) 200 mcg oral tablet Levoxyl (levothyroxine) 25 mcg oral tablet Levoxyl (levothyroxine) 50 mcg oral tablet Levoxyl (levothyroxine) 75 mcg oral tablet Levoxyl (levothyroxine) 88 mcg oral tablet liothyronine (Bulk) 100 % Powder liothyronine 10 mcg/mL IV liothyronine Sodium, 25 mcg, tablet, oral liothyronine Sodium, 5 mcg, tablet, oral liothyronine Sodium, 50 mcg, tablet, oral Liotrix, 120Mg, tablet, oral Liotrix, 15Mg, tablet, oral Liotrix, 180Mg, tablet, oral Liotrix, 30Mg, tablet, oral Liotrix, 60Mg, tablet, oral methimazole (Bulk) 100 % Powder methimazole 15 mg oral tablet methimazole 20 mg oral tablet methimazole, 10 mg, tablet, oral NP Thyroid (thyroid (pork)) 30 mg oral tablet NP Thyroid (thyroid (pork)) 60 mg oral tablet NP Thyroid (thyroid (pork)) 90 mg oral tablet Nature-Throid (thyroid (pork)) 113.75 mg oral tablet Nature-Throid (thyroid (pork)) 130 mg oral tablet Nature-Throid (thyroid (pork)) 146.25 mg oral tablet Nature-Throid (thyroid (pork)) 16.25 mg oral tablet  

5

Thyroid Circadian and Circannual Rhythms in Thyroid Hormones: Determining the TSH and Free T4 Reference Intervals Based Upon Time of Day, Age, and Sex. (doi: 10.1089/thy.2014.0589) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.

Version 4.3 May 2, 2015

Nature-Throid (thyroid (pork)) 162.5 mg oral   tablet Nature-Throid (thyroid (pork)) 195 mg oral tablet Nature-Throid (thyroid (pork)) 260 mg oral tablet Nature-Throid (thyroid (pork)) 32.5 mg oral tablet Nature-Throid (thyroid (pork)) 325 mg oral tablet Nature-Throid (thyroid (pork)) 48.75 mg oral tablet Nature-Throid (thyroid (pork)) 65 mg oral tablet Nature-Throid (thyroid (pork)) 81.25 mg oral tablet Nature-Throid (thyroid (pork)) 97.5 mg oral tablet Northyx (methimazole) 10 mg oral tablet Northyx (methimazole) 15 mg oral tablet Northyx (methimazole) 20 mg oral tablet Northyx (methimazole) 5 mg oral tablet propylthiouracil, 50 mg, tablet, oral Synthroid (Levothyroxine) 137 mcg oral tablet Synthroid (levothyroxine) 100 mcg oral tablet Synthroid (levothyroxine) 112 mcg oral tablet Synthroid (levothyroxine) 125 mcg oral tablet Synthroid (levothyroxine) 150 mcg oral tablet Synthroid (levothyroxine) 175 mcg oral tablet Synthroid (levothyroxine) 200 mcg oral tablet Synthroid (levothyroxine) 25 mcg oral tablet Synthroid (levothyroxine) 300 mcg oral tablet Synthroid (levothyroxine) 50 mcg oral tablet Synthroid (levothyroxine) 75 mcg oral tablet Synthroid (levothyroxine) 88 mcg oral tablet ihyroglobulin 65 mg, oral tablet ihryoid 60 mg oral table thyroid bovine, 120 mg, oral tablet thyroid bovine, 30 mg, oral tablet thyroid bovine, 60 mg, oral tablet thyroid pork, 25 mg, oral tablet thyroxine solution, topical Tapazole (methimazole) 10 mg oral tablet Tapazole (methimazole) 5 mg oral tablet thyroid (Bulk) Powder thyroid 120 mg oral tablet thyroid 130 mg oral tablet thyroid 15 mg oral tablet thyroid 180 mg oral tablet thyroid 195 mg oral tablet thyroid 240 mg oral tablet thyroid 30 mg oral tablet thyroid 300 mg oral tablet thyroid 32.5 mg oral tablet thyroid 60 mg oral tablet thyroid 65 mg oral tablet  

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Thyroid Circadian and Circannual Rhythms in Thyroid Hormones: Determining the TSH and Free T4 Reference Intervals Based Upon Time of Day, Age, and Sex. (doi: 10.1089/thy.2014.0589) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.

Version 4.3 May 2, 2015

thyroid 90 mg oral tablet   thyroid 120 mg, tablet, oral thyroid 15 mg, tablet, oral Thyroid 180 mg, tablet, oral thyroid 240 mg, tablet, oral thyroid pork (Bulk) 100 % Powder thyroid pork, 150Mg, Capsule, oral thyroid pork, 180Mg, Capsule, oral thyroid pork, 30Mg, Capsule, oral thyroid pork, 32.4mg, tablet, oral thyroid pork, 60Mg, Capsule, oral thyroid pork, 64.8mg, tablet, oral thyroid pork, 8Mg, Capsule, oral Thyrolar-1 (liotrix) 12.5-50 mcg oral tablet Thyrolar-1/2 (liotrix) 6.25-25 mcg oral tablet Thyrolar-1/4 (liotrix) 3.1-12.5 mcg oral tablet Thyrolar-2 (liotrix) 25-100 mcg oral tablet Thyrolar-3 (liotrix) 37.5-150 mcg oral tablet Tirosint (levothyroxine) 100 mcg oral Capsule Tirosint (levothyroxine) 112 mcg oral Capsule Tirosint (levothyroxine) 125 mcg oral Capsule Tirosint (levothyroxine) 13 mcg oral Capsule Tirosint (levothyroxine) 137 mcg oral Capsule Tirosint (levothyroxine) 150 mcg oral Capsule Tirosint (levothyroxine) 25 mcg oral Capsule Tirosint (levothyroxine) 50 mcg oral Capsule Tirosint (levothyroxine) 75 mcg oral Capsule Tirosint (levothyroxine) 88 mcg oral Capsule Triostat (liothyronine) 10 mcg/mL Intravenous Solution Unithroid (levothyroxine) 137 mcg oral tablet Unithroid (levothyroxine) 100 mcg oral tablet Unithroid (levothyroxine) 112 mcg oral tablet Unithroid (levothyroxine) 125 mcg oral tablet Unithroid (levothyroxine) 150 mcg oral tablet Unithroid (levothyroxine) 175 mcg oral tablet Unithroid (levothyroxine) 200 mcg oral tablet Unithroid (levothyroxine) 25 mcg oral tablet Unithroid (levothyroxine) 300 mcg oral tablet Unithroid (levothyroxine) 50 mcg oral tablet Unithroid (levothyroxine) 75 mcg oral tablet Unithroid (levothyroxine) 88 mcg oral tablet Westhroid (thyroid (pork)) 113.75 mg oral tablet Westhroid (thyroid (pork)) 130 mg oral tablet Westhroid (thyroid (pork)) 146.25 mg oral tablet Westhroid (thyroid (pork)) 16.25 mg oral tablet Westhroid (thyroid (pork)) 260 mg oral tablet Westhroid (thyroid (pork)) 32.5 mg oral tablet  

7

Thyroid Circadian and Circannual Rhythms in Thyroid Hormones: Determining the TSH and Free T4 Reference Intervals Based Upon Time of Day, Age, and Sex. (doi: 10.1089/thy.2014.0589) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.

Version 4.3 May 2, 2015

Westhroid (thyroid (pork)) 48.75 mg oral tablet   Westhroid (thyroid (pork)) 65 mg oral tablet Westhroid (thyroid (pork)) 81.25 mg oral tablet Westhroid (thyroid (pork)) 97.5 mg oral tablet Westhroid-P (thyroid (pork)) 32.5 mg oral tablet methimazole 5 mg tablet propylthiouracil 50 mg tablet thyroid (pork) 113.75 mg tablet thyroid (pork) 120 mg tablet thyroid (pork) 130 mg tablet thyroid (pork) 15 mg tablet thyroid (pork) 16.25 mg tablet thyroid (pork) 162.5 mg tablet thyroid (pork) 180 mg tablet thyroid (pork) 195 mg tablet thyroid (pork) 260 mg tablet thyroid (pork) 30 mg tablet thyroid (pork) 300 mg tablet thyroid (pork) 32.5 mg tablet thyroid (pork) 48.75 mg tablet thyroid (pork) 60 mg tablet thyroid (pork) 65 mg tablet thyroid (pork) 81.25 mg tablet thyroid (pork) 90 mg tablet thyroid (pork) 97.5 mg tablet thyroid pork (bulk) 100 % USP Powder

 

8

Thyroid Circadian and Circannual Rhythms in Thyroid Hormones: Determining the TSH and Free T4 Reference Intervals Based Upon Time of Day, Age, and Sex. (doi: 10.1089/thy.2014.0589) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.

Version 4.3 May 2, 2015

  Supplemental Table 2 TSH (mIU/L) Reference Interval by Age, Sex, and Hour

Age Band Sex Hour 00:00 01:00 02:00 03:00 04:00 05:00 06:00 07:00 08:00 09:00 10:00 11:00 12:00 13:00 14:00 15:00 16:00 17:00 18:00 19:00 20:00 21:00 22:00 23:00

 

1-20

21-40

M

F

0.540-6.5 0.569-6.6 0.606-6.7 0.646-6.7 0.683-6.6 0.712-6.4 0.730-6.2 0.730-5.8 0.708-5.4 0.660-5.0 0.599-4.5 0.581-4.6 0.570-4.6 0.561-4.5 0.560-4.4 0.562-4.4 0.558-4.4 0.550-4.6 0.539-4.8 0.528-5.1 0.519-5.4 0.513-5.7 0.513-6.0 0.522-6.3

0.58-6.4 0.61-6.5 0.64-6.5 0.67-6.4 0.70-6.3 0.71-6.1 0.72-5.8 0.71-5.4 0.68-5.1 0.63-4.6 0.57-4.3 0.56-4.4 0.55-4.4 0.53-4.3 0.53-.2 0.53-4.1 0.53-4.1 0.53-4.3 0.53-4.5 0.53-4.9 0.53-5.2 0.53-5.6 0.54-5.9 0.56-6.2

M 0.52-6.0 0.54-6.0 0.55-5.9 0.58-5.8 0.60-5.6 0.61-5.4 0.62-5.1 0.63-4.9 0.62-4.6 0.61-4.3 0.58-4.1 0.55-4.2 0.53-4.3 0.53-4.2 0.53-4.2 0.52-4.2 0.52-4.3 0.51-4.5 0.51-4.7 0.50-5.0 0.50-5.2 0.50-5.5 0.50-5.7 0.51-5.9

41-60 F

0.54-5.8 0.56-5.9 0.58-5.8 0.60-5.8 0.62-5.6 0.63-5.4 0.64-5.2 0.63-5.0 0.61-4.7 0.58-4.4 0.54-4.2 0.53-4.2 0.52-4.2 0.51-4.1 0.51-4.1 0.52-4.2 0.52-4.3 0.52-4.4 0.52-4.6 0.52-4.9 0.52-5.1 0.52-5.3 0.52-5.5 0.53-5.7

M

F TSH mIU/L 0.57-5.9 0.55-6.9 0.59-5.9 0.56-6.8 0.60-5.8 0.57-6.6 0.62-5.6 0.59-6.3 0.63-5.5 0.60-6.0 0.64-5.2 0.61-5.6 0.65-5.0 0.61-5.3 0.64-4.8 0.61-5.0 0.68-4.6 0.60-4.7 0.60-4.4 0.58-4.5 0.57-4.3 0.55-4.5 0.57-4.3 0.54-4.6 0.56-4.4 0.53-4.7 0.55-4.5 0.52-4.7 0.54-4.5 0.52-4.7 0.54-4.6 0.52-4.8 0.54-4.8 0.53-4.9 0.54-4.9 0.53-5.1 0.54-5.1 0.53-5.4 0.54-5.3 0.53-5.7 0.54-5.5 0.53-6.1 0.54-5.7 0.53-6.4 0.55-5.8 0.54-6.7 0.56-5.9 0.54-6.8

9

61-80

80+

M

F

M

F

0.48-6.7 0.50-6.7 0.53-6.6 0.56-6.4 0.60-6.1 0.63-5.8 0.65-5.5 0.66-5.2 0.65-5.0 0.62-4.8 0.58-4.7 0.58-4.6 0.57-4.6 0.55-4.6 0.55-4.6 0.56-4.7 0.56-4.8 0.55-5.1 0.54-5.3 0.519-5.6 0.500-5.9 0.484-6.2 0.473-6.5 0.470-6.6

0.53-7.6 0.56-7.5 0.58-7.4 0.61-7.1 0.63-6.8 0.65-6.4 0.66-6.0 0.66-5.6 0.64-5.3 0.61-5.0 0.56-4.7 0.52-4.7 0.51-4.8 0.52-4.9 0.52-4.9 0.52-5.0 0.52-5.2 0.51-5.4 0.51-5.8 0.51-6.2 0.50-6.6 0.51-6.9 0.51-7.2 0.52-7.5

0.565-6.7 0.597-6.7 0.634-6.7 0.672-6.7 0.705-6.6 0.730-6.5 0.740-6.3 0.732-6.1 0.700-5.9 0.640-5.7 0.569-5.5 0.560-5.7 0.576-5.5 0.590-5.2 0.588-5.2 0.575-5.4 0.560-5.7 0.546-5.9 0.534-6.1 0.525-6.3 0.520-6.4 0.520-6.5 0.527-6.6 0.541-6.7

0.51-6.9 0.52-6.9 0.53-7.0 0.54-6.9 0.55-6.8 0.56-6.7 0.57-6.5 0.57-6.2 0.57-6.0 0.57-5.7 0.56-5.6 0.54-5.7 0.54-5.6 0.55-5.4 0.55-5.3 0.54-5.3 0.53-5.3 0.52-5.5 0.51-5.7 0.51-5.9 0.51-6.1 0.50-6.4 0.51-6.6 0.51-6.8

Thyroid Circadian and Circannual Rhythms in Thyroid Hormones: Determining the TSH and Free T4 Reference Intervals Based Upon Time of Day, Age, and Sex. (doi: 10.1089/thy.2014.0589) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.

Version 4.3 May 2, 2015

 

  Supplemental Table 3A: TSH Reference Interval Median by Age, Sex, Hour, and Ethnicity

Lower Limit

Hour 00:00

01:00

02:00

03:00

04:00

 

GENDER AGE BAND Race Native American Asian AfroAmerican Pacific Islander Other Caucasian Native American Asian AfroAmerican Pacific Islander Other Caucasian Native American Asian AfroAmerican Pacific Islander Other Caucasian Native American Asian AfroAmerican Pacific Islander Other Caucasian Native American Asian Afro-

M 1-20

21-40

0.56 0.51

0.53 0.46

0.58 0.54

0.65 0.4

0.69 0.61

0.49

0.49

0.54

0.42

0.53 0.54 0.54

0.54 0.53 0.52

0.57 0.58 0.57

0.59 0.54

0.56 0.47

0.52

41-60

61-80

>80

F 1-20

21-40

41-60

61-80

>80

0.59 0.55

0.55 0.47

0.57 0.52

0.72 0.47

0.59 0.51

0.82

0.53

0.5

0.53

0.49

0.73

0.45 0.47 0.48

0.53 0.62 0.61

0.57 0.58 0.58

0.55 0.54 0.53

0.55 0.57 0.56

0.51 0.54 0.55

0.43 0.52 0.52

0.61 0.55

0.68 0.41

0.72 0.63

0.63 0.57

0.57 0.48

0.59 0.53

0.75 0.48

0.6 0.51

0.5

0.55

0.44

0.85

0.56

0.52

0.53

0.5

0.73

0.54 0.57 0.57

0.53 0.55 0.53

0.56 0.59 0.59

0.44 0.49 0.5

0.54 0.65 0.65

0.58 0.61 0.61

0.55 0.56 0.55

0.54 0.57 0.57

0.51 0.56 0.57

0.42 0.53 0.52

0.63 0.57

0.58 0.48

0.63 0.56

0.71 0.44

0.76 0.66

0.67 0.6

0.6 0.5

0.6 0.54

0.77 0.5

0.61 0.52

0.55

0.52

0.56

0.46

0.88

0.59

0.53

0.54

0.52

0.73

0.55 0.6 0.61

0.53 0.56 0.55

0.55 0.61 0.61

0.44 0.51 0.53

0.55 0.68 0.68

0.59 0.64 0.64

0.54 0.58 0.57

0.53 0.58 0.58

0.51 0.57 0.59

0.4 0.53 0.53

0.67 0.6

0.6 0.5

0.65 0.57

0.74 0.46

0.8 0.69

0.7 0.63

0.62 0.52

0.62 0.54

0.8 0.51

0.62 0.52

0.59

0.53

0.58

0.49

0.91

0.62

0.55

0.55

0.54

0.74

0.57 0.64 0.65

0.52 0.58 0.58

0.55 0.62 0.62

0.45 0.54 0.56

0.55 0.71 0.71

0.6 0.67 0.68

0.54 0.6 0.59

0.52 0.59 0.59

0.5 0.59 0.62

0.38 0.53 0.54

0.71 0.63 0.62

0.62 0.51 0.55

0.66 0.58 0.59

0.78 0.49 0.52 10

0.82 0.71 0.93

0.73 0.66 0.64

0.64 0.53 0.57

0.63 0.55 0.55

0.81 0.53 0.55

0.63 0.52 0.74

Thyroid Circadian and Circannual Rhythms in Thyroid Hormones: Determining the TSH and Free T4 Reference Intervals Based Upon Time of Day, Age, and Sex. (doi: 10.1089/thy.2014.0589) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.

Version 4.3 May 2, 2015

05:00

06:00

07:00

08:00

09:00

 

American Pacific Islander Other Caucasian Native American Asian AfroAmerican Pacific Islander Other Caucasian Native American Asian AfroAmerican Pacific Islander Other Caucasian Native American Asian AfroAmerican Pacific Islander Other Caucasian Native American Asian AfroAmerican Pacific Islander Other Caucasian Native American Asian AfroAmerican Pacific Islander

  0.58 0.67 0.68

0.52 0.59 0.6

0.54 0.63 0.64

0.46 0.57 0.6

0.56 0.73 0.74

0.61 0.69 0.71

0.54 0.61 0.61

0.5 0.6 0.6

0.5 0.61 0.64

0.37 0.54 0.55

0.73 0.66

0.63 0.53

0.66 0.59

0.8 0.52

0.83 0.73

0.75 0.68

0.65 0.54

0.63 0.55

0.82 0.54

0.64 0.53

0.64

0.56

0.59

0.54

0.94

0.66

0.58

0.55

0.56

0.74

0.59 0.69 0.71

0.52 0.61 0.61

0.53 0.63 0.65

0.48 0.6 0.63

0.56 0.74 0.75

0.61 0.71 0.73

0.54 0.62 0.63

0.49 0.6 0.61

0.5 0.62 0.65

0.36 0.54 0.56

0.74 0.67

0.64 0.54

0.66 0.59

0.82 0.54

0.83 0.73

0.75 0.68

0.65 0.55

0.63 0.55

0.83 0.55

0.64 0.53

0.65

0.57

0.59

0.55

0.93

0.66

0.58

0.55

0.56

0.74

0.6 0.71 0.73

0.52 0.62 0.63

0.52 0.64 0.65

0.49 0.62 0.65

0.55 0.74 0.76

0.61 0.72 0.74

0.53 0.63 0.64

0.49 0.6 0.61

0.49 0.62 0.66

0.36 0.55 0.57

0.73 0.67

0.64 0.54

0.65 0.59

0.82 0.55

0.8 0.71

0.73 0.67

0.64 0.54

0.61 0.55

0.81 0.54

0.63 0.54

0.64

0.56

0.57

0.56

0.91

0.64

0.57

0.54

0.55

0.74

0.6 0.71 0.73

0.53 0.62 0.63

0.52 0.63 0.65

0.5 0.63 0.66

0.53 0.72 0.74

0.6 0.71 0.73

0.53 0.63 0.63

0.48 0.6 0.61

0.49 0.62 0.65

0.36 0.55 0.57

0.7 0.65

0.62 0.54

0.62 0.57

0.8 0.54

0.75 0.67

0.69 0.64

0.61 0.53

0.59 0.54

0.79 0.53

0.62 0.54

0.61

0.55

0.55

0.54

0.86

0.6

0.54

0.52

0.53

0.73

0.59 0.69 0.71

0.53 0.62 0.62

0.52 0.62 0.63

0.51 0.62 0.65

0.5 0.69 0.7

0.58 0.68 0.7

0.53 0.61 0.62

0.49 0.59 0.6

0.49 0.61 0.64

0.38 0.56 0.57

0.64 0.61

0.59 0.52

0.58 0.55

0.76 0.52

0.67 0.61

0.62 0.59

0.56 0.5

0.56 0.53

0.75 0.5

0.61 0.55

0.56

0.52

0.51

0.51

0.79

0.53

0.5

0.49

0.49

0.72

0.57

0.55

0.52

0.51

0.47

0.55

0.52

0.49

0.49

0.4

11

Thyroid Circadian and Circannual Rhythms in Thyroid Hormones: Determining the TSH and Free T4 Reference Intervals Based Upon Time of Day, Age, and Sex. (doi: 10.1089/thy.2014.0589) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.

Version 4.3 May 2, 2015

10:00

11:00

12:00

13:00

14:00

15:00

 

Other Caucasian Native American Asian AfroAmerican Pacific Islander Other Caucasian Native American Asian AfroAmerican Pacific Islander Other Caucasian Native American Asian AfroAmerican Pacific Islander Other Caucasian Native American Asian AfroAmerican Pacific Islander Other Caucasian Native American Asian AfroAmerican Pacific Islander Other Caucasian Native

0.66 0.66

0.61 0.61

 0.6 0.6

0.61 0.63

0.63 0.63

0.63 0.64

0.59 0.58

0.58 0.58

0.59 0.61

0.57 0.57

0.57 0.56

0.55 0.5

0.54 0.53

0.71 0.49

0.59 0.54

0.54 0.53

0.51 0.47

0.52 0.51

0.69 0.47

0.59 0.54

0.5

0.49

0.48

0.47

0.71

0.47

0.46

0.47

0.45

0.72

0.55 0.6 0.6

0.55 0.59 0.58

0.52 0.58 0.57

0.51 0.58 0.59

0.43 0.56 0.56

0.52 0.57 0.57

0.51 0.55 0.54

0.5 0.56 0.55

0.48 0.55 0.57

0.43 0.56 0.56

0.54 0.56

0.51 0.49

0.52 0.54

0.7 0.5

0.57 0.56

0.52 0.53

0.5 0.48

0.5 0.52

0.64 0.45

0.55 0.54

0.52

0.5

0.51

0.5

0.75

0.49

0.49

0.49

0.44

0.73

0.53 0.58 0.59

0.52 0.55 0.55

0.52 0.56 0.57

0.5 0.56 0.59

0.42 0.55 0.56

0.51 0.55 0.56

0.51 0.54 0.54

0.49 0.54 0.55

0.44 0.5 0.53

0.4 0.53 0.54

0.52 0.55

0.48 0.48

0.5 0.54

0.67 0.49

0.58 0.58

0.49 0.53

0.47 0.47

0.47 0.51

0.62 0.44

0.54 0.54

0.52

0.5

0.52

0.5

0.78

0.49

0.49

0.49

0.45

0.74

0.51 0.57 0.58

0.5 0.54 0.54

0.5 0.56 0.57

0.47 0.54 0.57

0.43 0.57 0.58

0.48 0.54 0.55

0.49 0.53 0.53

0.47 0.53 0.53

0.42 0.49 0.52

0.4 0.53 0.54

0.5 0.54

0.47 0.48

0.48 0.52

0.63 0.47

0.58 0.59

0.46 0.5

0.44 0.45

0.45 0.49

0.61 0.44

0.54 0.55

0.51

0.5

0.51

0.48

0.79

0.48

0.47

0.48

0.45

0.75

0.5 0.56 0.57

0.5 0.54 0.54

0.49 0.56 0.56

0.45 0.53 0.55

0.45 0.59 0.59

0.47 0.53 0.53

0.47 0.52 0.51

0.46 0.52 0.52

0.43 0.51 0.53

0.41 0.55 0.55

0.49 0.54

0.46 0.48

0.47 0.52

0.63 0.47

0.57 0.58

0.45 0.5

0.43 0.45

0.44 0.49

0.61 0.45

0.53 0.55

0.51

0.5

0.51

0.48

0.79

0.47

0.48

0.48

0.46

0.75

0.52 0.56 0.57 0.49

0.51 0.54 0.53 0.45

0.5 0.55 0.55 0.47

0.47 0.53 0.55 0.64

0.46 0.58 0.58 0.55

0.48 0.52 0.53 0.45

0.49 0.52 0.51 0.44

0.47 0.52 0.52 0.45

0.45 0.51 0.53 0.61

0.42 0.55 0.55 0.52

12

Thyroid Circadian and Circannual Rhythms in Thyroid Hormones: Determining the TSH and Free T4 Reference Intervals Based Upon Time of Day, Age, and Sex. (doi: 10.1089/thy.2014.0589) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.

Version 4.3 May 2, 2015

16:00

17:00

18:00

19:00

20:00

 

American Asian AfroAmerican Pacific Islander Other Caucasian Native American Asian AfroAmerican Pacific Islander Other Caucasian Native American Asian AfroAmerican Pacific Islander Other Caucasian Native American Asian AfroAmerican Pacific Islander Other Caucasian Native American Asian AfroAmerican Pacific Islander Other Caucasian Native American Asian Afro-

  0.54

0.47

0.52

0.48

0.57

0.51

0.46

0.5

0.45

0.54

0.52

0.5

0.51

0.5

0.78

0.48

0.49

0.49

0.46

0.75

0.54 0.56 0.56

0.53 0.53 0.53

0.52 0.54 0.55

0.5 0.54 0.56

0.46 0.56 0.57

0.5 0.52 0.53

0.51 0.52 0.52

0.5 0.52 0.53

0.47 0.51 0.53

0.43 0.53 0.54

0.49 0.54

0.45 0.47

0.47 0.52

0.65 0.49

0.54 0.56

0.46 0.51

0.45 0.47

0.45 0.51

0.61 0.45

0.51 0.53

0.52

0.5

0.51

0.51

0.77

0.49

0.5

0.5

0.47

0.74

0.55 0.55 0.56

0.54 0.52 0.52

0.54 0.54 0.54

0.52 0.54 0.57

0.47 0.55 0.56

0.52 0.52 0.53

0.54 0.52 0.52

0.52 0.52 0.53

0.48 0.5 0.53

0.44 0.52 0.53

0.48 0.53

0.45 0.47

0.47 0.52

0.65 0.49

0.54 0.55

0.46 0.51

0.46 0.47

0.46 0.51

0.61 0.45

0.51 0.53

0.51

0.5

0.52

0.5

0.77

0.49

0.5

0.51

0.47

0.74

0.56 0.54 0.55

0.55 0.52 0.52

0.55 0.54 0.54

0.53 0.53 0.56

0.48 0.54 0.55

0.53 0.52 0.53

0.55 0.52 0.52

0.54 0.53 0.53

0.5 0.5 0.52

0.45 0.51 0.52

0.48 0.52

0.46 0.46

0.48 0.52

0.65 0.47

0.55 0.55

0.47 0.51

0.46 0.47

0.48 0.51

0.62 0.45

0.52 0.52

0.5

0.49

0.52

0.49

0.76

0.49

0.5

0.51

0.47

0.73

0.56 0.53 0.54

0.55 0.51 0.51

0.56 0.54 0.54

0.53 0.52 0.55

0.48 0.54 0.54

0.54 0.52 0.53

0.56 0.52 0.52

0.55 0.53 0.53

0.51 0.5 0.52

0.45 0.51 0.51

0.48 0.51

0.46 0.45

0.49 0.52

0.64 0.46

0.56 0.55

0.48 0.51

0.47 0.46

0.49 0.51

0.63 0.45

0.52 0.52

0.49

0.49

0.52

0.48

0.76

0.49

0.5

0.51

0.47

0.73

0.55 0.52 0.53

0.56 0.51 0.5

0.57 0.54 0.54

0.52 0.51 0.53

0.49 0.54 0.54

0.55 0.52 0.53

0.57 0.52 0.51

0.56 0.53 0.54

0.51 0.5 0.52

0.46 0.51 0.51

0.49 0.5 0.48

0.47 0.45 0.48

0.51 0.52 0.52

0.63 0.44 0.46

0.57 0.55 0.76

0.5 0.51 0.49

0.48 0.46 0.49

0.5 0.52 0.52

0.64 0.45 0.47

0.53 0.51 0.73

13

Thyroid Circadian and Circannual Rhythms in Thyroid Hormones: Determining the TSH and Free T4 Reference Intervals Based Upon Time of Day, Age, and Sex. (doi: 10.1089/thy.2014.0589) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.

Version 4.3 May 2, 2015

21:00

22:00

23:00

 

American Pacific Islander Other Caucasian Native American Asian AfroAmerican Pacific Islander Other Caucasian Native American Asian AfroAmerican Pacific Islander Other Caucasian Native American Asian AfroAmerican Pacific Islander Other Caucasian

  0.55 0.52 0.52

0.56 0.51 0.5

0.57 0.54 0.54

0.51 0.49 0.51

0.49 0.54 0.55

0.55 0.52 0.53

0.57 0.52 0.51

0.57 0.54 0.54

0.52 0.5 0.52

0.46 0.51 0.51

0.5 0.49

0.48 0.45

0.52 0.52

0.63 0.42

0.59 0.56

0.51 0.51

0.49 0.46

0.52 0.52

0.66 0.45

0.55 0.51

0.48

0.48

0.52

0.44

0.77

0.49

0.49

0.52

0.47

0.72

0.54 0.51 0.51

0.55 0.51 0.5

0.57 0.55 0.54

0.49 0.48 0.49

0.5 0.56 0.55

0.56 0.53 0.53

0.56 0.52 0.51

0.57 0.54 0.54

0.52 0.51 0.52

0.45 0.51 0.51

0.51 0.49

0.5 0.45

0.54 0.53

0.63 0.4

0.62 0.57

0.53 0.52

0.51 0.46

0.54 0.52

0.68 0.45

0.56 0.51

0.47

0.48

0.53

0.43

0.78

0.5

0.49

0.52

0.47

0.72

0.54 0.52 0.51

0.55 0.52 0.5

0.57 0.56 0.55

0.47 0.47 0.48

0.51 0.57 0.57

0.56 0.54 0.54

0.56 0.53 0.51

0.57 0.55 0.54

0.52 0.51 0.53

0.45 0.51 0.51

0.53 0.5

0.51 0.45

0.56 0.53

0.64 0.4

0.65 0.59

0.56 0.53

0.52 0.46

0.55 0.52

0.7 0.46

0.57 0.51

0.48

0.48

0.53

0.42

0.8

0.51

0.49

0.52

0.48

0.72

0.53 0.53 0.52

0.54 0.52 0.51

0.57 0.57 0.56

0.46 0.47 0.48

0.52 0.59 0.59

0.56 0.56 0.55

0.55 0.53 0.52

0.56 0.56 0.55

0.52 0.53 0.54

0.44 0.52 0.51

14

Thyroid Circadian and Circannual Rhythms in Thyroid Hormones: Determining the TSH and Free T4 Reference Intervals Based Upon Time of Day, Age, and Sex. (doi: 10.1089/thy.2014.0589) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.

Version 4.3 May 2, 2015

Supplemental Table 3B:   TSH Reference Interval Median by Age, Sex, Hour, and Ethnicity

       

Upper Limit

Hour 0:00

1:00

2:00

3:00

4:00

 

GENDER AGE BAND Race Native American Asian AfroAmerican Pacific Islander Other Caucasian Native American Asian AfroAmerican Pacific Islander Other Caucasian Native American Asian AfroAmerican Pacific Islander Other Caucasian Native American Asian AfroAmerican Pacific Islander Other Caucasian Native American

M

F

1-20

21-40

41-60

61-80

>80

1-20

21-40

41-60

61-80

>80

       

6.83 6.16

5.93 5.25

6.8 5.05

7.52 5.94

5.28 5.34

6.82 6.15

6.19 5.51

7.28 5.53

8.01 6.43

5.54 5.61

       

6.27

4.98

5.32

6.26

4.77

6.26

5.24

5.8

6.75

5.04

   

4.6 6.02 6.6

4.07 5.79 5.75

4.11 6.18 6.07

4.51 7.29 6.87

8.95 7.06 6.62

4.59 6.01 6.59

4.33 6.05 6.01

4.59 6.66 6.55

5 7.78 7.36

9.22 7.32 6.89

           

6.9 6.36

5.9 5.36

6.69 5.08

7.44 6

5.27 5.47

6.88 6.34

6.15 5.61

7.17 5.55

7.93 6.48

5.52 5.73

       

6.3

4.92

5.19

6.15

4.73

6.29

5.18

5.66

6.63

4.99

   

4.93 6.14 6.74

4.3 5.82 5.79

4.26 6.13 6.03

4.69 7.27 6.86

9.2 7.11 6.68

4.91 6.13 6.72

4.55 6.07 6.04

4.73 6.6 6.5

5.17 7.76 7.35

9.46 7.37 6.94

           

6.8 6.5

5.72 5.41

6.42 5.04

7.17 5.96

5.13 5.57

6.75 6.45

5.95 5.65

6.87 5.49

7.63 6.42

5.37 5.81

       

6.21

4.75

4.92

5.88

4.6

6.16

4.98

5.37

6.34

4.84

   

5.3 6.22 6.79

4.59 5.81 5.76

4.46 6.03 5.91

4.89 7.17 6.74

9.54 7.15 6.7

5.25 6.17 6.75

4.82 6.04 5.99

4.91 6.48 6.36

5.35 7.63 7.2

9.77 7.38 6.93

           

6.57 6.56

5.44 5.42

6.04 4.95

6.76 5.85

4.92 5.65

6.49 6.48

5.63 5.62

6.45 5.36

7.18 6.27

5.11 5.85

       

6.01

4.5

4.57

5.51

4.42

5.93

4.69

4.98

5.93

4.62

   

5.66 6.24 6.76

4.9 5.78 5.67

4.67 5.9 5.72

5.07 7.01 6.53

9.92 7.18 6.68

5.58 6.16 6.68

5.09 5.97 5.87

5.08 6.31 6.14

5.49 7.43 6.95

10.11 7.38 6.88

           

6.26

5.1

5.61

6.28

4.66

6.14

5.25

5.98

6.66

4.81

   

15

Thyroid Circadian and Circannual Rhythms in Thyroid Hormones: Determining the TSH and Free T4 Reference Intervals Based Upon Time of Day, Age, and Sex. (doi: 10.1089/thy.2014.0589) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.

Version 4.3 May 2, 2015

5:00

6:00

7:00

8:00

9:00

 

Asian AfroAmerican Pacific Islander Other Caucasian Native American Asian AfroAmerican Pacific Islander Other Caucasian Native American Asian AfroAmerican Pacific Islander Other Caucasian Native American Asian AfroAmerican Pacific Islander Other Caucasian Native American Asian AfroAmerican Pacific Islander Other Caucasian Native American Asian

6.54

5.38  

4.81

5.66

5.68

6.42

5.53

5.18

6.04

5.83

   

5.76

4.22

4.2

5.08

4.22

5.64

4.37

4.56

5.46

4.37

   

5.96 6.2 6.65

5.17 5.71 5.53

4.85 5.74 5.49

5.2 6.8 6.25

10.27 7.19 6.62

5.84 6.07 6.52

5.32 5.86 5.68

5.22 6.11 5.86

5.58 7.18 6.63

10.42 7.35 6.77

           

5.92 6.43

4.76 5.27

5.2 4.63

5.8 5.41

4.4 5.66

5.75 6.26

4.86 5.38

5.52 4.96

6.14 5.75

4.51 5.77

       

5.48

3.94

3.85

4.67

4.03

5.31

4.05

4.17

5

4.13

   

6.15 6.1 6.46

5.37 5.61 5.35

4.97 5.57 5.23

5.26 6.57 5.93

10.55 7.18 6.52

5.98 5.93 6.29

5.47 5.72 5.45

5.29 5.89 5.55

5.59 6.9 6.26

10.65 7.29 6.63

           

5.58 6.22

4.46 5.11

4.85 4.42

5.39 5.13

4.19 5.57

5.36 6.01

4.52 5.17

5.13 4.7

5.67 5.42

4.25 5.64

       

5.21

3.72

3.57

4.32

3.88

5

3.78

3.85

4.61

3.94

   

6.18 5.93 6.19

5.43 5.49 5.13

4.99 5.4 4.96

5.21 6.33 5.58

10.69 7.14 6.37

5.96 5.72 5.98

5.49 5.55 5.19

5.27 5.68 5.24

5.49 6.62 5.87

10.76 7.2 6.44

           

5.29 5.91

4.26 4.88

4.64 4.18

5.1 4.81

4.05 5.41

5.04 5.66

4.28 4.9

4.88 4.43

5.35 5.06

4.07 5.44

       

4.99

3.58

3.43

4.1

3.81

4.74

3.6

3.67

4.35

3.84

   

5.98 5.71 5.85

5.33 5.35 4.87

4.87 5.25 4.7

5.01 6.1 5.24

10.65 7.06 6.19

5.73 5.45 5.6

5.35 5.37 4.89

5.11 5.49 4.94

5.26 6.35 5.49

10.68 7.09 6.21

           

5.09 5.48

4.2 4.58

4.62 3.93

5 4.48

4.03 5.16

4.82 5.2

4.19 4.58

4.83 4.15

5.22 4.71

4.03 5.16

       

4.85

3.57

3.47

4.06

3.85

4.58

3.57

3.68

4.29

3.85

   

5.52 5.41 5.44

5 5.18 4.59

4.58 5.13 4.46

4.65 5.9 4.93

10.37 6.94 5.95

5.24 5.13 5.16

4.99 5.18 4.59

4.8 5.34 4.68

4.87 6.13 5.15

10.37 6.94 5.95

           

5.03 4.93

4.32 4.21

4.84 3.66

5.16 4.15

4.17 4.81

4.75 4.64

4.31 4.2

5.05 3.87

5.38 4.37

4.16 4.8

       

16

Thyroid Circadian and Circannual Rhythms in Thyroid Hormones: Determining the TSH and Free T4 Reference Intervals Based Upon Time of Day, Age, and Sex. (doi: 10.1089/thy.2014.0589) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.

Version 4.3 May 2, 2015

10:00

11:00

12:00

13:00

14:00

 

AfroAmerican Pacific Islander Other Caucasian Native American Asian AfroAmerican Pacific Islander Other Caucasian Native American Asian AfroAmerican Pacific Islander Other Caucasian Native American Asian AfroAmerican Pacific Islander Other Caucasian Native American Asian AfroAmerican Pacific Islander Other Caucasian Native American Asian AfroAmerican

 

4.83

3.74

3.73

4.26

4.03

4.55

3.73

3.94

4.48

4.02

   

4.73 5.04 4.95

4.4 5 4.29

4.08 5.04 4.26

4.08 5.75 4.66

9.78 6.77 5.67

4.45 4.75 4.67

4.39 4.99 4.28

4.29 5.25 4.47

4.3 5.97 4.88

9.78 6.77 5.66

           

5.09 4.48

4.55 3.93

5.2 3.51

5.43 3.91

4.43 4.56

4.81 4.2

4.54 3.92

5.41 3.72

5.65 4.13

4.42 4.55

       

4.76

3.84

3.96

4.4

4.16

4.48

3.83

4.17

4.62

4.15

   

4.05 4.67 4.56

3.88 4.8 4.07

3.7 4.97 4.17

3.61 5.59 4.48

9.3 6.6 5.48

3.77 4.39 4.28

3.87 4.79 4.06

3.91 5.18 4.38

3.83 5.81 4.7

9.29 6.6 5.47

           

5.05 4.77

4.45 4.16

5.15 3.79

5.21 4.02

4.46 4.91

4.75 4.47

4.42 4.13

5.34 3.98

5.41 4.22

4.43 4.89

       

4.18

3.2

3.37

3.64

3.65

3.88

3.17

3.56

3.84

3.62

   

4.64 4.55 4.71

4.41 4.62 4.15

4.28 4.84 4.3

4.02 5.29 4.44

9.96 6.55 5.68

4.34 4.25 4.4

4.38 4.59 4.12

4.47 5.03 4.49

4.22 5.49 4.64

9.93 6.52 5.66

           

4.85 4.91

4.23 4.28

5.02 4

5.07 4.22

4.09 4.89

4.55 4.61

4.2 4.25

5.21 4.19

5.27 4.42

4.06 4.86

       

4.11

3.11

3.37

3.63

3.41

3.81

3.08

3.56

3.83

3.38

   

4.41 4.56 4.72

4.16 4.61 4.14

4.12 4.92 4.39

3.85 5.36 4.52

9.56 6.39 5.53

4.11 4.26 4.42

4.13 4.58 4.12

4.31 5.11 4.58

4.05 5.56 4.72

9.53 6.37 5.5

           

4.5 4.78

3.95 4.22

4.84 4.04

4.95 4.32

3.57 4.59

4.21 4.49

3.93 4.2

5.04 4.24

5.16 4.53

3.55 4.57

       

4.28

3.34

3.71

4.03

3.41

3.99

3.32

3.91

4.24

3.39

   

3.7 4.57 4.57

3.52 4.69 4.06

3.58 5.11 4.41

3.37 5.61 4.6

8.68 6.24 5.21

3.41 4.28 4.28

3.5 4.67 4.04

3.78 5.3 4.6

3.58 5.81 4.8

8.66 6.22 5.19

           

4.07 4.57

3.61 4.11

4.55 3.98

4.63 4.23

3.18 4.43

3.76 4.26

3.58 4.08

4.74 4.16

4.83 4.43

3.15 4.4

       

4.15

3.32

3.72

4.02

3.33

3.85

3.29

3.91

4.22

3.3

   

17

Thyroid Circadian and Circannual Rhythms in Thyroid Hormones: Determining the TSH and Free T4 Reference Intervals Based Upon Time of Day, Age, and Sex. (doi: 10.1089/thy.2014.0589) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.

Version 4.3 May 2, 2015

15:00

16:00

17:00

18:00

19:00

 

Pacific Islander Other Caucasian Native American Asian AfroAmerican Pacific Islander Other Caucasian Native American Asian AfroAmerican Pacific Islander Other Caucasian Native American Asian AfroAmerican Pacific Islander Other Caucasian Native American Asian AfroAmerican Pacific Islander Other Caucasian Native American Asian AfroAmerican Pacific Islander

 

3.5 4.53 4.43

3.42 4.75 4.03

3.52 5.21 4.41

3.29 5.68 4.58

8.53 6.25 5.13

3.19 4.23 4.13

3.39 4.72 4

3.71 5.39 4.6

3.48 5.88 4.78

8.5 6.22 5.1

           

3.72 4.39

3.36 4.04

4.3 3.9

4.32 4.09

2.99 4.41

3.4 4.07

3.32 3.99

4.47 4.07

4.5 4.27

2.95 4.37

       

3.9

3.16

3.57

3.8

3.23

3.58

3.12

3.74

3.98

3.19

   

3.65 4.49 4.38

3.67 4.81 4.08

3.77 5.26 4.46

3.48 5.68 4.56

8.84 6.36 5.23

3.33 4.17 4.06

3.63 4.76 4.03

3.95 5.44 4.63

3.66 5.86 4.75

8.79 6.32 5.19

           

3.62 4.33

3.32 4.03

4.26 3.89

4.26 4.07

2.99 4.44

3.31 4.02

3.28 3.99

4.44 4.07

4.45 4.26

2.95 4.4

       

3.81

3.13

3.54

3.76

3.24

3.5

3.09

3.72

3.94

3.2

   

3.8 4.51 4.44

3.88 4.89 4.19

3.98 5.35 4.58

3.67 5.74 4.66

9.08 6.48 5.38

3.49 4.2 4.13

3.84 4.85 4.15

4.16 5.53 4.76

3.85 5.93 4.85

9.04 6.44 5.35

           

3.77 4.38

3.48 4.09

4.43 3.97

4.46 4.17

3.14 4.5

3.48 4.09

3.46 4.08

4.63 4.17

4.67 4.38

3.13 4.49

       

3.92

3.25

3.67

3.91

3.36

3.63

3.23

3.87

4.13

3.34

   

3.9 4.61 4.6

3.98 5 4.36

4.1 5.46 4.76

3.81 5.89 4.87

9.18 6.59 5.55

3.61 4.32 4.31

3.96 4.98 4.34

4.3 5.67 4.96

4.02 6.1 5.09

9.17 6.57 5.54

           

4.1 4.53

3.78 4.21

4.74 4.09

4.85 4.37

3.42 4.59

3.85 4.28

3.81 4.23

4.99 4.34

5.1 4.62

3.44 4.61

       

4.18

3.47

3.91

4.22

3.55

3.93

3.5

4.15

4.47

3.58

   

3.95 4.76 4.84

4.01 5.12 4.57

4.14 5.6 4.98

3.92 6.1 5.17

9.18 6.68 5.73

3.7 4.51 4.59

4.03 5.14 4.59

4.38 5.84 5.22

4.17 6.35 5.42

9.21 6.7 5.76

           

4.57 4.75

4.18 4.36

5.16 4.26

5.36 4.64

3.77 4.69

4.36 4.54

4.25 4.43

5.45 4.55

5.66 4.93

3.84 4.76

       

4.53

3.77

4.21

4.63

3.79

4.33

3.84

4.5

4.93

3.87

   

3.99

3.98

4.13

4.01

9.11

3.79

4.06

4.42

4.31

9.18

   

18

Thyroid Circadian and Circannual Rhythms in Thyroid Hormones: Determining the TSH and Free T4 Reference Intervals Based Upon Time of Day, Age, and Sex. (doi: 10.1089/thy.2014.0589) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.

Version 4.3 May 2, 2015

20:00

21:00

22:00

23:00

 

Other Caucasian Native American Asian AfroAmerican Pacific Islander Other Caucasian Native American Asian AfroAmerican Pacific Islander Other Caucasian Native American Asian AfroAmerican Pacific Islander Other Caucasian Native American Asian AfroAmerican Pacific Islander Other Caucasian

4.96 5.13

5.25   4.8

5.74 5.22

6.34 5.51

6.76 5.91

4.76 4.93

5.32 4.87

6.03 5.51

6.64 5.81

6.83 5.98

       

5.1 5.01

4.63 4.54

5.61 4.45

5.93 4.94

4.15 4.81

4.95 4.86

4.76 4.67

5.95 4.79

6.28 5.29

4.28 4.93

       

4.95

4.1

4.55

5.08

4.06

4.8

4.22

4.89

5.43

4.18

   

4.04 5.18 5.46

3.94 5.38 5.04

4.09 5.88 5.47

4.08 6.59 5.87

9 6.83 6.09

3.89 5.03 5.31

4.06 5.51 5.16

4.43 6.22 5.81

4.44 6.94 6.22

9.12 6.95 6.21

           

5.65 5.31

5.08 4.74

6.06 4.64

6.5 5.25

4.54 4.94

5.55 5.21

5.25 4.91

6.45 5.03

6.9 5.65

4.71 5.11

       

5.37

4.42

4.87

5.52

4.32

5.27

4.59

5.26

5.92

4.49

   

4.1 5.41 5.79

3.9 5.51 5.27

4.04 6.01 5.7

4.16 6.84 6.22

8.89 6.89 6.25

4 5.31 5.69

4.07 5.69 5.44

4.44 6.4 6.09

4.56 7.24 6.62

9.07 7.07 6.43

           

6.16 5.61

5.48 4.93

6.44 4.82

6.99 5.54

4.88 5.07

6.11 5.56

5.7 5.15

6.88 5.25

7.44 5.98

5.1 5.29

       

5.76

4.7

5.13

5.9

4.54

5.71

4.92

5.57

6.34

4.76

   

4.2 5.64 6.11

3.89 5.63 5.48

4.02 6.11 5.89

4.25 7.05 6.52

8.83 6.95 6.4

4.14 5.58 6.05

4.11 5.84 5.69

4.45 6.54 6.32

4.69 7.5 6.96

9.04 7.17 6.62

           

6.58 5.9

5.78 5.1

6.71 4.96

7.36 5.78

5.14 5.21

6.55 5.88

6.03 5.35

7.17 5.42

7.83 6.26

5.39 5.46

       

6.08

4.9

5.3

6.16

4.7

6.05

5.15

5.76

6.64

4.95

   

4.36 5.84 6.39

3.94 5.72 5.64

4.03 6.17 6.02

4.36 7.21 6.75

8.83 7.01 6.53

4.33 5.82 6.36

4.18 5.97 5.89

4.5 6.63 6.48

4.84 7.69 7.22

9.08 7.26 6.78

           

19

Thyroid Circadian and Circannual Rhythms in Thyroid Hormones: Determining the TSH and Free T4 Reference Intervals Based Upon Time of Day, Age, and Sex. (doi: 10.1089/thy.2014.0589) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.

Version 4.3 May 2, 2015

Supplemental Table 4  

time 0:00

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GENDER AGE BAND Self-Described Ethnicity American Indian Asian Afro-American Hawaiian Other Caucasian American Indian Asian Afro-American Hawaiian Other Caucasian American Indian Asian Afro-American Hawaiian Other Caucasian American Indian Asian Afro-American Hawaiian Other Caucasian American Indian Asian Afro-American Hawaiian Other Caucasian American Indian Asian Afro-American Hawaiian Other Caucasian American Indian Asian

F 1-21

21-40

41-60

61-80

1 4 0 2 82 233 2 1 1 1 41 153 1 0 2 2 13 94 1 1 3 2 14 55 1 1 3 0 1 37 1 0 1 0 12 38 0 0

6 6 6 10 165 536 6 4 9 6 119 385 2 2 0 2 35 169 3 1 2 3 24 107 1 2 2 4 18 113 1 2 2 3 23 90 4 3

2 4 2 1 114 284 2 4 0 2 66 212 1 1 2 0 14 87 0 1 1 4 7 57 2 2 0 1 9 48 3 0 1 2 19 126 4 1

0 3 0 2 26 102 0 1 1 0 16 80 1 1 0 0 16 43 0 0 0 0 14 66 1 0 0 1 19 76 0 0 0 4 14 93 4 0

20

>80

M 1-20

21-40

41-60

61-80

>80

0 0 0 0 3 14 0 0 0 0 1 10 0 0 0 0 1 21 0 0 0 0 6 40 0 1 0 0 11 44 0 1 0 0 14 54 0 1

1 1 4 2 37 147 0 0 4 0 25 101 0 1 2 0 11 68 2 0 1 2 15 42 0 1 1 0 12 41 0 0 1 0 4 31 2 1

2 3 5 2 107 288 0 2 8 1 74 203 1 1 8 1 20 116 0 0 2 1 20 86 4 1 2 0 32 85 1 0 0 1 60 112 7 1

1 2 5 2 87 200 0 2 2 2 49 109 0 0 1 0 19 66 3 0 0 1 6 70 1 0 1 0 15 54 3 0 1 2 43 134 3 0

1 0 0 0 24 62 0 0 0 0 4 50 1 1 0 0 7 34 0 0 0 0 8 45 1 0 0 0 5 49 0 0 0 0 15 76 2 2

0 0 0 0 1 9 0 0 0 0 0 7 0 0 0 0 1 17 0 0 0 0 2 17 0 0 0 0 3 24 0 0 0 0 4 25 0 0

Thyroid Circadian and Circannual Rhythms in Thyroid Hormones: Determining the TSH and Free T4 Reference Intervals Based Upon Time of Day, Age, and Sex. (doi: 10.1089/thy.2014.0589) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.

Version 4.3 May 2, 2015

7:00

8:00

9:00

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Afro-American Hawaiian Other Caucasian American Indian Asian Afro-American Hawaiian Other Caucasian American Indian Asian Afro-American Hawaiian Other Caucasian American Indian Asian Afro-American Hawaiian Other Caucasian American Indian Asian Afro-American Hawaiian Other

6 3 41 81 6 3 21 3 299 573 8 15 20 11 247 1063 12 23 26 20 423 1907 17 35 43 27 656

Caucasian American Indian Asian Afro-American Hawaiian Other Caucasian American Indian Asian Afro-American Hawaiian Other Caucasian American Indian Asian Afro-American

2621 14 31 43 20 726 2743 11 32 37 10 545 2396 6 16 26

2   3 84 227 6 21 5 25 234 1447 34 108 41 52 945 5020 65 252 74 111 2215 9917 68 264 75 115 2657 1076 7 53 208 101 115 2368 9604 58 143 72 72 1600 6680 23 90 43

4 3 131 414 16 47 12 9 376 2702 49 251 37 52 1360 9150 73 384 98 91 2689 13248 84 294 82 132 2666

0 1 26 243 4 21 2 4 128 1278 11 89 11 29 469 5580 18 178 33 35 953 8670 20 131 26 46 954

0 0 10 47 0 2 2 0 19 174 0 14 1 0 52 683 1 15 0 4 130 1222 3 22 7 5 143

8 1 55 98 5 5 34 2 374 534 8 7 13 2 188 737 11 14 23 11 309 1171 17 21 28 10 397

2 3 159 276 11 12 9 10 179 966 19 63 35 26 844 3626 23 84 56 48 1366 5108 31 92 50 62 1347

2 1 163 352 7 24 21 15 253 2251 25 129 59 46 1301 7822 38 184 81 87 1972 9373 32 125 62 93 1632

2 2 27 195 5 23 3 6 97 1446 10 76 15 19 552 5638 14 93 28 36 887 7438 18 78 24 31 711

0 0 6 32 0 1 0 0 8 177 1 8 2 1 52 688 1 19 4 2 64 1021 0 3 3 2 96

11560 58 248 61 94 2109 8768 38 141 58 61 1383 5668 24 72 30

8025 22 76 31 50 784 6080 15 50 26 21 495 3687 2 35 9

1387 2 18 4 4 128 1405 1 14 1 3 80 913 0 10 5

1543 12 21 19 20 358 1446 8 14 26 13 287 1139 6 18 15

4218 18 72 46 47 1036 3234 13 44 30 36 613 2302 8 28 16

6646 24 91 55 42 1180 4560 16 45 33 33 773 2757 4 27 22

5970 9 48 14 27 507 4137 6 26 11 12 317 2390 4 14 11

1052 1 6 2 2 73 865 0 8 2 0 66 546 0 8 2

21

Thyroid Circadian and Circannual Rhythms in Thyroid Hormones: Determining the TSH and Free T4 Reference Intervals Based Upon Time of Day, Age, and Sex. (doi: 10.1089/thy.2014.0589) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.

Version 4.3 May 2, 2015

14:00

15:00

16:00

17:00

18:00

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Hawaiian Other Caucasian American Indian Asian Afro-American Hawaiian Other Caucasian American Indian Asian Afro-American Hawaiian Other Caucasian American Indian Asian Afro-American Hawaiian Other Caucasian American Indian Asian Afro-American Hawaiian Other Caucasian American Indian Asian Afro-American Hawaiian Other Caucasian American Indian Asian Afro-American Hawaiian Other Caucasian American Indian Asian Afro-American Hawaiian Other

12 398 1660 17 39 45 29 583 2391 20 48 37 22 738 3074 21 42 43 25 685 3009 3 25 30 12 383 1695 7 9 7 4 179 677 5 4 12 4 140 412 2 4 9 4 101

42   1156 4301 50 141 81 51 1851 6954 72 131 58 65 1834 7233 38 118 67 55 1605 6015 20 58 36 27 726 3219 8 20 13 16 533 1594 7 23 16 15 416 1040 8 11 11 12 244

54 853 3358 22 124 49 42 1250 4817 35 102 42 51 1306 4918 21 81 38 25 1114 4048 14 38 12 7 513 1973 9 15 9 12 339 989 4 16 3 10 289 694 9 5 5 10 209

22

9 283 2052 10 38 16 23 402 3056 5 36 15 13 423 2925 4 38 11 8 281 1870 2 14 2 8 141 847 0 4 3 3 95 373 3 6 3 3 61 277 0 6 1 0 51

2 53 549 1 13 4 1 93 855 1 15 1 3 115 793 0 11 5 1 76 548 0 4 0 0 35 246 0 2 0 0 13 95 0 1 0 0 15 64 0 1 0 0 9

11 250 855 17 8 28 9 343 1242 12 19 22 9 438 1439 15 14 30 14 398 1493 6 6 24 9 202 849 4 8 9 3 114 357 3 3 6 3 92 271 1 2 3 0 43

22 505 1500 8 30 36 19 755 2217 17 41 39 28 778 2314 10 21 30 22 672 2035 8 13 13 9 349 1146 3 8 10 8 311 749 1 7 5 4 261 543 0 2 9 8 154

19 437 1730 19 43 43 29 742 2551 20 25 29 27 784 2661 10 29 21 24 618 2253 7 16 13 7 325 1077 2 3 5 5 300 650 7 6 9 5 221 476 3 1 9 5 122

9 212 1411 13 29 14 16 320 2156 6 17 5 10 328 2055 3 10 4 8 246 1325 3 5 3 3 111 619 2 3 1 3 63 316 2 3 1 3 74 229 0 1 0 0 50

0 39 323 0 6 5 1 65 525 1 5 1 1 73 502 0 2 1 0 42 363 0 0 0 1 19 161 0 0 0 0 8 53 0 1 1 0 4 33 0 0 0 0 3

Thyroid Circadian and Circannual Rhythms in Thyroid Hormones: Determining the TSH and Free T4 Reference Intervals Based Upon Time of Day, Age, and Sex. (doi: 10.1089/thy.2014.0589) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.

Version 4.3 May 2, 2015

21:00

22:00

23:00

 

Caucasian American Indian Asian Afro-American Hawaiian Other Caucasian American Indian Asian Afro-American Hawaiian Other Caucasian American Indian Asian Afro-American Hawaiian Other Caucasian

338 4 2 5 5 61 249 5 1 10 4 82 242 1 6 7 4 69 257

766   1 10 14 9 176 580 3 5 9 8 252 580 5 3 5 6 201 593

434 6 4 3 4 141 325 6 6 4 3 190 360 3 3 3 2 151 288

189 1 1 4 2 34 131 0 2 1 2 66 130 0 2 0 0 40 114

23

38 0 0 0 0 3 31 0 0 2 0 9 38 0 1 0 0 3 36

198 2 3 8 1 53 156 0 2 3 1 39 145 2 0 6 0 26 160

366 4 2 6 2 116 295 1 4 9 5 123 311 9 0 10 3 115 286

274 7 3 9 3 79 218 2 0 2 2 100 195 1 4 3 2 110 189

132 0 1 0 1 20 94 0 0 2 0 41 92 0 1 0 0 23 74

33 0 1 0 1 2 22 0 0 0 0 5 16 0 0 0 0 4 18

Thyroid Circadian and Circannual Rhythms in Thyroid Hormones: Determining the TSH and Free T4 Reference Intervals Based Upon Time of Day, Age, and Sex. (doi: 10.1089/thy.2014.0589) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.

TSH Circadian Reference Interval by Gender, Age, and Time of Day.

Thyroid Circadian and Circannual Rhythms in Thyroid Hormones: Determining the TSH and Free T4 Reference Intervals Based Upon Time of Day, Age, and Sex. (doi: 10.1089/thy.2014.0589) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.

TSH Circannual Reference Interval by Age.

Thyroid Circadian and Circannual Rhythms in Thyroid Hormones: Determining the TSH and Free T4 Reference Intervals Based Upon Time of Day, Age, and Sex. (doi: 10.1089/thy.2014.0589) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.

Free T4 Circadian Variation by Age and Gender

Thyroid Circadian and Circannual Rhythms in Thyroid Hormones: Determining the TSH and Free T4 Reference Intervals Based Upon Time of Day, Age, and Sex. (doi: 10.1089/thy.2014.0589) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.

Free T4 Circannual Variation by Age.