Thyroid-stimulating Hormone Reference Intervals Research Articles

Establishing the TSH reference intervals for healthy adults aged over 70 years: the Australian ASPREE cohort study.

As thyroid disorders are common amongst the elderly, this study aims to evaluate the reference interval (RI) for thyroid stimulating hormone (TSH) in healthy adults aged 70 years and over. A proposed RI was determined from the Australian participants of the ASPirin in Reducing Events in the Elderly (ASPREE) randomised trial. Participants had nohistory of cardiovascular disease, thyroid cancer, dementia, or life-threatening illnesses. Participants prescribed with any thyroid-related medication at baseline were excluded. TSH levels were measured using a commercial chemiluminescence microparticle immunoassay. The RI was determined using the middle 95th percentile of the logarithmic transformed data of baseline TSH. Cox proportional hazard regression models were used to validate the RI by assessing disease incidence over time. A total of 10,995 participants had baseline TSH measures. Median (IQR) age was 73.9 (71.8-77.3) years. We propose a RI of 0.34-3.75 mU/L. TSH levels did not differ by age or sex. At baseline, there was no association between symptoms associated with thyroid disease and levels of TSH. Over the follow-up period of up to 11 years, no association was seen between baseline TSH levels and relevant disease outcomes for participants within the RI. From a group of initially healthy, community-dwelling adults aged >=70 years, we propose a RI of TSH to best represent euthyroidism. This concentration was not associated with an increased risk of thyroid related symptoms or outcomes, confirming its appropriateness for clinical use.

B-114 Reference interval (RI) estimation for TSH in adults using an indirect method with unsupervised machine learning tool and R programming language

Abstract Background Thyroid-stimulating hormone (TSH) plays a fundamental role in regulating thyroid hormones T3 (triiodothyronine) and T4 (thyroxine). Understanding TSH test results is essential for effective management of thyroid disorders and depends, among other factors, on establishing specific reference intervals (RI) for the population being served. We aimed to estimate the reference intervals for TSH in the adult population served by a large diagnostic network in Brazil. Methods We employed data mining followed by estimation using an indirect method through the LabRI™ algorithm with parametric, non-parametric, and robust statistical treatments for outlier exclusion, a series of algorithms programmed in R Language. Included were TSH values from outpatients, aged 20 to 60 years, both sexes, from two analytical platforms. Used as a comparative RI recommended by the American Thyroid Association (ATA, 2014). Data were extracted from the Data Lake, from January to December 2022, from two laboratories in Brazil. Exclusion criteria: samples from hospital sources and referral laboratories; pregnant; some laboratory tests correlated with de TSH test; samples from patients using thyroid hormone and medications that may interfere with hormonal function and TSH laboratory analysis. Results After exclusion criteria, the sample totaled 26,909 adults of both sexes. After excluding 2.24% outliers, the estimated RI was 0.67-4.26 mIU/L, with the comparative RI chosen for this study being the one recommended by ATA of 0.40-4.00 mIU/L. The RI obtained in our study was similar to the Canadian RI harmonization study for TSH (0.60-4.48 mIU/L). Conclusions We estimated the RI, harmonized between Roche and Siemens platforms, to be 0.67-4.26 mIU/L. The RI obtained by the LabRI™ tool is equivalent to the Adeli study (2023) and is under discussion by the company's endocrinology committee for whether to use the estimated RI from our internal study or the one recommended by ATA (2014) in reports.

Age-specific reference intervals for TSH and FT4 to optimize diagnosis of thyroid disease.

Background Thyroid-stimulating hormone (TSH) and subsequent free thyroxine (FT4) concentrations outside the reference interval (RI) are used to diagnose thyroid diseases. Most laboratories do not provide age-specific RIs for TSH and FT4 beyond childhood, although TSH concentrations vary with age. Therefore, we aimed to establish TSH and FT4 age-specific RIs throughout life and aimed to determine whether using these RIs would result in reclassification of thyroid disease diagnoses in adults. Methods This multicenter retrospective cross-sectional study used big data to determine indirect RIs for TSH and FT4. These RIs were determined by TMC and refineR-analysis, respectively, using four different immunoassay platforms (Roche, Abbott, Siemens, Beckman Coulter). Retrospective data (2008-2022) from 13 Dutch laboratories for general practitioners and local hospitals were used. RIs were evaluated per manufacturer. Age groups were established from 2-20 years by 2-year categories and decade categories between 20 and 100 years. Results We included totally 7.6 million TSH and 2.2 million FT4 requests. TSH upper reference limits (URLs) and FT4 lower reference limits (LRLs) were higher in early childhood and decreased towards adulthood. In adulthood, TSH URLs increased from 60 years in men, and from 50 years in women, while FT4 URLs increased from 70 years onwards. Using adult age-specific RIs resulted in a decrease in diagnoses of subclinical and overt hypothyroidism in women above 50 and men above 60 years in our Roche dataset. Conclusion This study stressed the known importance of using age-specific RIs for TSH and FT4 in children. This study also showed the clinical relevance of using age-specific RIs for TSH in adulthood to reduce diagnoses of subclinical hypothyroidism in older persons. Therefore, implementation of adult TSH age-specific RIs should be strongly considered. Data is less uniform regarding FT4 age-specific RIs and more research should be performed before implementing these in clinical practice.

Harnessing the Power of Big Data Analytics-Estimation of Reference Intervals for Neonatal Serum TSH in Pakistan Using RefineR Algorithm.

To estimate the population-specific reference intervals (RIs) for neonatal thyroid stimulating hormone (TSH) in Pakistani neonates, utilising the refineR algorithm. Observational study. Place and Duration of the Study: Department of Pathology and Laboratory Medicine, The Aga Khan University Hospital, Karachi, Pakistan, from 17th May to 30th November 2023. A data mining analysis was conducted on serum TSH results of neonates (≤1 month) over a period of six years, following approval from the Institutional Ethical Review Committee. Two subgroups were assessed based on the age as 0 - 5 days and 6 - 30 days. The refineR algorithm was implemented using refineR package (version 1.0.0), ensuring accurate analysis and insights. A total of non-duplicate 82,299 neonatal serum TSH tests were retrieved, including 70,788 (88%) aged 0 - 5 days and 11,511 (12%) aged ranging from 6 - 30 days. The estimated RI was from 0.67 µIU/mL (90% CI 0.641 - 0.72) to 15.0 µIU/mL (90% CI 13.2 - 17.3) for the first age group and 0.65 µIU/mL (90% CI 0.6 - 0.84) to 8.6 µIU/mL (90% CI 8.05 - 9.71) for the second age group. Reference intervals for neonatal serum TSH of the Pakistani population were estimated, considering the genetic differences of this demographic in comparison to the Western population. Results aligned with global literature, validating the refineR indirect approach's applicability. Reference intervals, Neonatal, Thyroid stimulating hormone, RefineR algorithm, Big data, Pakistan.

Defining Trimester-Specific Reference Intervals for Thyroid Hormones: Insights from a Bulgarian Monocenter Study.

Background and Objectives: Pregnancy introduces various interfering factors that, alongside individual variations, impact the assessment of thyroid function tests. This underscores the necessity of defining trimester-specific reference intervals for thyroid-stimulating hormone (TSH) levels. Differences in population characteristics, including ethnicity, socio-economic factors, iodine prophylaxis, and obesity, emphasize the need to establish trimester-specific TSH ranges for women of reproductive age in the respective region or center. The aim of the present study was to establish first- and second-trimester-specific reference intervals for TSH and free thyroxine (FT4) in a relevant pregnant population. Materials and Methods: A retrospective monocenter analysis utilized the electronic database of Ob/Gyn Hospital "Dr. Shterev", Sofia, Bulgaria. The analysis involved data from 497 pregnant and 250 non-pregnant women, all without evidence of thyroid dysfunction or a family history thereof, no indication of taking medication interfering with thyroid function, no evidence of levothyroxine treatment, and no history of sterility treatment. To establish the limits of the TSH reference range, the percentile method was applied using a bootstrapping procedure following the recommendations of the International Federation of Clinical Chemistry (IFCC). Results: Trimester-specific reference intervals for TSH and FT4 in our center were established as follows: first trimester-0.38-2.91 mU/L, FT4-12.18-19.48 pmol/L; second trimester-0.72-4.22 mIU/L and 9.64-17.39 pmol/L, respectively. We also established the normal reference range for the non-pregnant control group, which is similar to that applicable in our laboratory. Conclusions: Our results differ from the fixed limits recommended by the American Thyroid Association, European Thyroid Association, and Endocrine Society Guidelines. Following the relevant established intervals would significantly impact timely diagnosis and therapy requirements for a substantial proportion of pregnant women.

Reference intervals for thyroid function from the fifth to seventh day of life in twin-pregnancy preterm neonates: an 8-year retrospective study.

The immature and developing hypothalamic-pituitary-thyroid axis leads to different levels of thyroid function in twin neonates, including free thyroxine (FT4), free triiodothyronine (FT3), and thyroid stimulating hormone (TSH) levels. No reference intervals for twins have been established until now. To compensate for this lack, we collected data and established this standard across different gestational ages (GAs) and sexes. A total of 273 pairs of neonates admitted to the NICU in Southeast China from 2015 to 2022 were included. Each pair was divided into Neonate A (relatively heavy birth weight (BW)) and Neonate B (relatively light BW). Their thyroid functions were analyzed to establish reference intervals and comparisons were made stratified by GA and sex. The FT3, FT4, and TSH reference intervals in twin neonates with a GA of 26-36 weeks were as follows: Neonate A and B: 3.59 ± 0.99 and 3.57 ± 1.00 pmol/L; Neonate A and B: 17.03 ± 5.16 and 16.77 ± 5.29 pmol/L; and Neonate A and B: 4.097 ± 3.688 and 4.674 ± 4.850 mlU/L, respectively. There were significant differences between serum FT3 and FT4 reference intervals and GA (p < 0.05). The serum FT3 and FT4 reference intervals for male neonates were lower than those for female neonates in the 29-32-week group (p < 0.05). This was the first study, to our knowledge, to establish reference intervals for thyroid function in twin neonates from the fifth to seventh day of life, which will be beneficial for the diagnosis and management of congenital hypothyroidism.

Should we depend on reference intervals from manufacturer package inserts? Comparing TSH and FT4 reference intervals from four manufacturers with results from modern indirect methods and the direct method.

Correct interpretation of thyroid function tests relies on correct reference intervals (RIs) for thyroid-stimulating hormone (TSH) and free thyroxine (FT4). ISO15189 mandates periodic verification of RIs, but laboratories struggle with cost-effective approaches. We investigated whether indirect methods (utilizing historical laboratory data) could replace the direct approach (utilizing healthy reference individuals) and compared results with manufacturer-provided RIs for TSH and FT4. We collected historical data (2008-2022) from 13 Dutch laboratories to re-establish RIs by employing indirect methods, TMC (for TSH) and refineR (for FT4). Laboratories used common automated platforms (Roche, Abbott, Beckman or Siemens). Indirect RIs (IRIs) were determined perlaboratory per year and clustered per manufacturer (>1.000.000 data points per manufacturer). Direct RIs (DRIs) were established in 125 healthy individuals per platform. TSH IRIs remained robust over the years for all manufacturers. FT4 IRIs proved robust for three manufacturers (Roche, Beckman and Siemens), but the IRI upper reference limit (URL) of Abbott showed a decrease of 2 pmol/L from 2015. Comparison of the IRIs and DRIs for TSH and FT4 showed close agreement using adequate age-stratification. Manufacturer-provided RIs, notably Abbott, Roche and Beckman exhibited inappropriate URLs (overall difference of 0.5-1.0 µIU/mL) for TSH. For FT4, the URLs provided by Roche, Abbott and Siemens were overestimated by 1.5-3.5 pmol/L. These results underscore the importance of RI verification as manufacturer-provided RIs are often incorrect and RIs may not be robust. Indirect methods offercost-effective alternatives for laboratory-specific or platform-specific verification of RIs.

Establishment of Reference Interval of Thyroid Hormones and Autoantibodies: A Cross-sectional Study

Introduction: The accurate diagnosis of thyroid disease relies on the sensitivity and specificity of laboratory tests, which require specific reference intervals. Thyroid hormone levels can be influenced by factors such as age, gender, iodine intake and geographical region. Therefore, it is recommended for clinical laboratories to establish their own reference intervals. Aim: To establish reference intervals for Thyroid Stimulating Hormone (TSH), Free Thyroxine (FT4), Anti-thyroglobulin antibody (anti-TG), and Anti-Thyroid Peroxidase Antibody (antiTPO) in males and and females. Materials and Methods: A cross-sectional study was conducted in the Department of Biochemistry, Amrita Institute of Medical Sciences (AIMS), Kochi, India, from December 2021 to July 2022. The study included 217 apparently healthy subjects aged between 18 years and 60 years. TSH, FT4, anti-TPO, and anti-TG levels were analysed to establish reference values for males and females in the two age groups: 18-40 years and 41-60 years. Reference intervals for thyroid parameters were expressed as mean±Standard Deviation (SD), median, 2.5th and 97.5th percentiles. The Mann-Whitney U test was used to assess the statistical significance of thyroid parameters between gender and age groups. Results: The mean age in the female population was 38.24±11.64 years, while in the male population, it was 39.24±10.98 years. The reference intervals and cut-offs for TSH, FT4, anti-TG and anti-TPO in females were determined as 0.80-4.12 μIU/mL, 0.99- 1.57 ngm/mL, &lt;85.33 IU/mL and &lt;45.13 IU/mL, respectively. In males, the reference intervals and cut-offs for TSH, FT4, anti-TG and anti-TPO were determined as 0.51-5.09 μIU/mL, 1.03-1.79 ng/mL, &lt;87.09 IU/mL and &lt;33.88 IU/mL, respectively. There was a significant difference in anti-TPO (p-value=0.017) in males between the two age groups. A significant difference was also observed in FT4 (p-value=0.010) and anti-TPO (p-value=0.034) between males and females. Conclusion: The study successfully established reference intervals and cut-off values for TSH, FT4, anti-TG, and antiTPO. It was found that anti-TPO levels decrease significantly with age progression. Additionally, the reference interval for TSH was wider in the 41-60 years age group compared to the younger age group.

Measurement of salivary thyroid hormones using the LC-MS/MS technique in a clinical setting.

Saliva could be an attractive alternative to blood for assessing thyroid hormonal function. Our goal was to determine if the levels of thyroid hormones in saliva can accurately reflect a person's thyroid status and if they consistently correlate with the levels of the same hormones in the blood. We conducted a cross-sectional study. We enrolled a total of 109 participants with different thyroid conditions. We measured TSH (Thyroid-Stimulating Hormone), free T3 (fT3), and free T4 (fT4) in the blood using two different immunoassay methods: electrochemiluminescence immunoassay (ECLIA) and chemiluminescence immunoassay (CLIA). Saliva samples were collected using Salivette® tubes, and then we analyzed the levels of thyroid hormones in the saliva using liquid chromatography with tandem mass spectrometry (LC-MS/MS). Comparing salivary and serum levels of thyroid hormones, we observed significantly lower fT4 and higher fT3 levels in saliva (p < 0.001), regardless of the measurement method. We also found that salivary fT3 and fT4 levels were positively correlated in the entire group of participants (p < 0.001, R 0.575), as well as in those with TSH values within the normal reference range (p < 0.001, R 0.570). We further divided participants based on their TSH reference intervals and assessed the correlations between serum and salivary thyroid hormones within these groups. We also discovered that taking exogenous levothyroxine influenced the correlations between serum and salivary thyroid hormones. Thyroid antibodies did not have a significant impact on the levels of thyroid hormones in both serum and saliva. This study demonstrates that salivary thyroid hormones can partially reflect the levels of these hormones in the blood. Saliva may be a useful tool in a clinical setting for patients with thyroid antibodies, but it may not be as effective for those who are taking levothyroxine as a treatment.

B-123 Utilization of Five Data Mining Algorithms Combined with Simplified Preprocessing to Establish Reference Intervals of Thyroid Related Hormones for Nonelderly Adults

Abstract Background Despite the extensive research on data mining algorithms, there is still a lack of a standard protocol to evaluate the performance of the existing algorithms. Therefore, the study aims to provide a novel procedure that combines data mining algorithms and simplified preprocessing to establish reference intervals (RIs), with the performance of five algorithms assessed objectively as well. Methods The Test data set and the Reference data set are the two data sets derived from the population undergoing a physical examination. After the thyroid-related hormone including thyroid stimulating hormone (TSH), free triiodo-thyronine (FT3), total triiodo-thyronine (TT3), free thyroxine(FT4), and total thyroxine (TT4) were measured by an ADVIA Centaur XP chemiluminescence immunoassay analyzer, five data algorithms were used to calculated RIs. Hoffmann, Bhattacharya, Expectation Maximum (EM), kosmic, and refineR algorithms combined with two-step data preprocessing respectively were implemented in the Test data set to establish RIs for thyroid-related hormones. The first step is to conduct a random sampling strategy to balance the ratio of sex and age, and the second step is to identify the outliers of variables in each subgroup by the Tukey method. Algorithm-calculated RIs were compared with the standard RIs calculated by transformed parametric method from the Reference data set in which reference individuals were selected following strict inclusion and exclusion criteria. RIs partition were comprehensively determined by the multiple linear regression and variance component analysis. Objective assessment of the methods is implemented by the bias ratio (BR) matrix, of which the BR threshold was set to 0.375. Results The levels of the all five thyroid-related hormones are significantly different in sex, with the male having lower TSH and higher FT3, FT4, TT3, and TT4 compared to the female. Further analysis indicates the establishment of sex-specific RIs for FT3 and FT4. Standard RIs derived from the Reference data set by transformed parametric method are 0.801–4.221 μIU/L for TSH, 2.58–3.82 pg/mL for FT3, 0.98–1.53 ng/dL for FT4, 0.80–1.38 ng/mL for TT3, 5.46–10.05 g/dL for TT4, respectively. There is a high consistency between TSH RIs established by the EM algorithm and the standard TSH RIs (BR = 0.063), although EM algorithms seems to perform poor on other hormones with the BR higher than 0.375. RIs calculated by Hoffmann, Bhattacharya, and refineR methods for free and total triiodo-thyronine, free and total thyroxine respectively are close and matched the standard RIs. Conclusion An effective approach for objectively evaluating the performance of the algorithm based on the BR matrix is established. EM algorithm combined with simplified preprocessing can handle data with significant skewness, but its performance is limited in other scenarios. The other four algorithms perform well for data with Gaussian or near-Gaussian distribution. Using the appropriate algorithm based on the data distribution characteristics is recommended.

A-338 TSH Reference Range in the First Trimester in a Iodine Sufficient Population of Pregnant Women Attended by the Public Health System in Curitiba South of Brazil

Abstract Background Thyroid diseases are common among women of reproductive age, and the serum concentration of thyroid-stimulating hormone (TSH) is the most used index to assess thyroid function during pregnancy. Changes in thyroid function during pregnancy can have a clinical impact on a woman's health and pregnancy outcome, as well as interfere with fetal health and child development. An adequate thyroid function is essential for normal intrauterine development. When comparing the levels of TSH between pregnant and non-pregnant women, TSH levels are lower in pregnancy, mainly in the first trimester, with gradual increase during pregnancy. Although some guidelines propose fixed TSH reference values in pregnancy according to the gestational trimester, the main recommendation is to carry out a study of their local population due to the significant variation in TSH reference range levels in different populations and different assays. Therefore, it is necessary to determine values of a reference interval for TSH for the local population of pregnant women. This study aims to determine the normal reference range of TSH in the first trimester of gestation in the public health system pregnant women from Curitiba. Methods This is an ongoing prospective cohort study, with the population sample from the pregnant women using the public health system, with age &amp;gt;18 years old in Curitiba, South of Brazil. 383 pregnant women were invited to participate. After evaluate the exclusion criteria (gestational age more than 13 weeks, twin pregnancy, thyroid disease, iodine ingestion, identification of the samples in the laboratory), 225 pregnant women had the TSH measured by chemiluminescent immunoassay on Atellica IM Analyzer (Siemens Healthineers), as well as the TPO-ab presence, FreeT4 and Total T4. The 2.5, 50 end 97,5 TSH percentiles were estimated for the normal pregnant population. Results The mean gestational age was 8,6 weeks (standard deviation 2.33). From 225 pregnant women, 22 (9.8%) had TPO-ab positive. The 2.5 and 97.5 percentiles of TSH were 0.12 and 5.28 μIU/mL after using de exclusion criteria. The populational iodine status was sufficient. In the TPO-ab positive population was found a higher level of TSH. The proportion of TPO-ab positive was significantly higher in the population with TSH &amp;gt;2.5 μIU/mL. Conclusions This preliminary data shows the TSH reference range with levels higher than other regions, reinforcing to do not use fixed values of TSH from other populations to evaluate the thyroid function in pregnancy. Comparing to the laboratory reference for non-pregnant adult (0.48 to 5.60 μIU/mL), the recommended reduction of 0.5 μIU/mL on upper limit and 0.4 μIU/mL on the lower limit found similar values to our findings.

B-159 Data Mining With the Bhattacharya Method as a Tool for Reference Interval Determination in Populations With Thyroid Disorders

Abstract Background Establishing a precise reference interval (RI) is crucial for laboratory diagnosis, population studies, and aiding physicians in patient follow-up treatment. Data mining and Bhattacharya analysis can be an efficient and cost-effective way to determine RIs for thyroid disorders based on large datasets. Bhattacharya analysis is a simple resolution method that detects distributions into Gaussian components. Unlike traditional reference interval studies using parametric or non-parametric statistics, Bhattacharya analysis does not exclude results from an “unhealthy” population before analysis. This study aimed to define the RI for thyroid-stimulating hormone (TSH) and free thyroxine (fT4) from three distinct regions in São Paulo, Brazil, using the Bhattacharya method. Methods The study was a 20-month retrospective analysis of a large laboratory database in São Paulo from February/2021 to September/2022. Individuals aged 21 or older with available TSH or fT4 results were selected, including only outpatient results. Three groups from different regions (R1, R2, R3) were studied and the indirect Bhattacharya method was used to determine each region’s RI values. The midpoint, upper and lower reference limits (URL and LRL), were calculated, and a data plot was created using Microsoft Excel. One-way ANOVA was used for multiple group comparisons and results with *P &amp;lt; 0.01 were considered statistically significant. Results A total of 234 903 TSH and fT4 records were obtained. The three groups showed significant differences in their mean age and TSH and fT4 results (P &amp;lt; 0.001). The mean age was 49.41 ± 16.9 for R1, 46.9 ± 9.6 for R2, and 53 ± 16 years old for R3. The average TSH value for all three regions was 2.44 µIU/mL (SD 0.18, CV 7.2%), and the average fT4 value was 1.17 ng/dL (SD 0.06, CV 4.7%). The central bin was selected for the best data distribution and close to the average or median for each group. The derived RIs for R1, R2, and R3 were compared for consideration of a common RI. Other criteria, such as the best bin size and at least four bins for the graph curve, were also applied. Altogether, Bhattacharya’s analysis identified the following estimates from all collection points for TSH and fT4: TSH Average LRL 0.43 µIU/mL (SD 0.07, CV 16.6%)/TSH Average URL 6.45 µIU/mL (SD 0.85, CV 13.1%)/TSH Average Range 6.03 µIU/mL (SD 0.88, CV 14.6%)/fT4 Average LRL 0.82 ng/dL (SD 0.07, CV 8.1%)/fT4 Average URL 1.47 ng/dL (SD 0.07, CV 4.4%)/fT4 Average Range 0.65 ng/dL (SD 0.02, CV 3.5%). 9.7% of individuals in R3 had results outside the accepted RIs for TSH and fT4, compared to R2 as a standard population with the lowest possibility of relevant thyroid disorders. Conclusion Bhattacharya’s non-parametric method could be useful to determine reference values and laboratory analysis of populations with distinct characteristics. The study highlights the importance of choosing the correct control group in comparison studies, and the potential bias in unifying distinct regions to determine RIs. The low cost of data mining makes it possible for nearby laboratories to perform similar studies using the Bhattacharya method to establish RI results suitable for specific patient populations.

The optimal healthy ranges of thyroid function defined by the risk of cardiovascular disease and mortality: systematic review and individual participant data meta-analysis

Reference intervals of thyroid-stimulating hormone (TSH) and free thyroxine (FT4) are statistically defined by the 2·5-97·5th percentiles, without accounting for potential risk of clinical outcomes. We aimed to define the optimal healthy ranges of TSH and FT4 based on the risk of cardiovascular disease and mortality. This systematic review and individual participant data (IPD) meta-analysis identified eligible prospective cohorts through the Thyroid Studies Collaboration, supplemented with a systematic search via Embase, MEDLINE (Ovid), Web of science, the Cochrane Central Register of Controlled Trials, and Google Scholar from Jan 1, 2011, to Feb 12, 2017 with an updated search to Oct 13, 2022 (cohorts found in the second search were not included in the IPD). We included cohorts that collected TSH or FT4, and cardiovascular outcomes or mortality for adults (aged ≥18 years). We excluded cohorts that included solely pregnant women, individuals with overt thyroid diseases, and individuals with cardiovascular disease. We contacted the study investigators of eligible cohorts to provide IPD on demographics, TSH, FT4, thyroid peroxidase antibodies, history of cardiovascular disease and risk factors, medication use, cardiovascular disease events, cardiovascular disease mortality, and all-cause mortality. The primary outcome was a composite outcome including cardiovascular disease events (coronary heart disease, stroke, and heart failure) and all-cause mortality. Secondary outcomes were the separate assessment of cardiovascular disease events, all-cause mortality, and cardiovascular disease mortality. We performed one-step (cohort-stratified Cox models) and two-step (random-effects models) meta-analyses adjusting for age, sex, smoking, systolic blood pressure, diabetes, and total cholesterol. The study was registered with PROSPERO, CRD42017057576. We identified 3935 studies, of which 53 cohorts fulfilled the inclusion criteria and 26 cohorts agreed to participate. We included IPD on 134 346 participants with a median age of 59 years (range 18-106) at baseline. There was a J-shaped association of FT4 with the composite outcome and secondary outcomes, with the 20th (median 13·5 pmol/L [IQR 11·2-13·9]) to 40th percentiles (median 14·8 pmol/L [12·3-15·0]) conveying the lowest risk. Compared with the 20-40th percentiles, the age-adjusted and sex-adjusted hazard ratio (HR) for FT4 in the 80-100th percentiles was 1·20 (95% CI 1·11-1·31) for the composite outcome, 1·34 (1·20-1·49) for all-cause mortality, 1·57 (1·31-1·89) for cardiovascular disease mortality, and 1·22 (1·11-1·33) for cardiovascular disease events. In individuals aged 70 years and older, the 10-year absolute risk of composite outcome increased over 5% for women with FT4 greater than the 85th percentile (median 17·6 pmol/L [IQR 15·0-18·3]), and men with FT4 greater than the 75th percentile (16·7 pmol/L [14·0-17·4]). Non-linear associations were identified for TSH, with the 60th (median 1·90 mIU/L [IQR 1·68-2·25]) to 80th percentiles (2·90 mIU/L [2·41-3·32]) associated with the lowest risk of cardiovascular disease and mortality. Compared with the 60-80th percentiles, the age-adjusted and sex-adjusted HR of TSH in the 0-20th percentiles was 1·07 (95% CI 1·02-1·12) for the composite outcome, 1·09 (1·05-1·14) for all-cause mortality, and 1·07 (0·99-1·16) for cardiovascular disease mortality. There was a J-shaped association of FT4 with cardiovascular disease and mortality. Low concentrations of TSH were associated with a higher risk of all-cause mortality and cardiovascular disease mortality. The 20-40th percentiles of FT4 and the 60-80th percentiles of TSH could represent the optimal healthy ranges of thyroid function based on the risk of cardiovascular disease and mortality, with more than 5% increase of 10-year composite risk identified for FT4 greater than the 85th percentile in women and men older than 70 years. We propose a feasible approach to establish the optimal healthy ranges of thyroid function, allowing for better identification of individuals with a higher risk of thyroid-related outcomes. None.

Thyroid Hormone Reference Intervals among Healthy Individuals In Lanzhou, China.

The common reference intervals (RIs) for thyroid hormones currently used in China are provided by equipment manufacturers. This study aimed to establish thyroid hormone RIs in the population of Lanzhou, a city in the subplateau region of northwest China, and compare them with previous reports and manufacturer-provided values. In total, 3,123 individuals (1,680 men, 1,443 women) from Lanzhou, an iodine-adequate area of China, perceived as healthy were selected. The Abbott Architect analyzer was used to determine the serum concentration of thyroid hormones. The 95% RI was estimated using the 2.5th and 97.5th percentiles as the lower and upper reference limits, respectively. The serum levels of thyroid-stimulating hormone (TSH), total triiodothyronine (TT3), antithyroglobulin (ATG) antibody, and antithyroid peroxidase (ATPO) antibody levels were significantly correlated with sex (P<0.05). TSH, total thyroxine (TT4), and ATPO levels were significantly correlated with age (P<0.05). The serum levels of TSH, ATG, and ATPO in men were significantly lower than in women; in contrast, the serum TT3 level was significantly higher in men than in women (P<0.05). Serum TSH, TT3, TT4, and ATG levels differed across age groups (P<0.05), but no such variation was observed for ATG levels (P>0.05). The established RIs of TSH, ATG, and ATPO in this study differed between sexes (P<0.05). The thyroid hormone RIs established herein were inconsistent with the manufacturer-provided values. The RIs of thyroid hormones in the healthy population of Lanzhou were inconsistent with those in the manufacturer's manual. Validated sex-specific values are required for diagnosing thyroid diseases.

Neonatal reference intervals for thyroid stimulating hormone and free thyroxine assayed on a Siemens Atellica® IM analyzer: a cross sectional study

BackgroundDeriving population specific reference intervals (RIs) or at the very least verifying any RI before adoption is good laboratory practice. Siemens has provided RIs for thyroid stimulating hormone (TSH) and free thyroxine (FT4) determined on their Atellica® IM analyzer for all age groups except the neonatal age group which provides a challenge for laboratories that intend to use it to screen for congenital hypothyroidism (CH) and other thyroid disorders in neonates. We set out to determine RIs for TSH and FT4 using data obtained from neonates undergoing routine screening for CH at the Aga Khan University Hospital, Nairobi, Kenya.MethodologyTSH and FT4 data for neonates aged 30 days and below were extracted from the hospital management information system for the period March 2020 to June 2021. A single episode of testing for the same neonate was included provided both TSH and FT4 were done on the same sample. RI determination was performed using a non-parametric approach.ResultsA total of 1243 testing episodes from 1218 neonates had both TSH and FT4 results. A single set of test results from each neonate was used to derive RIs. Both TSH and FT4 declined with increase in age with a more marked decline seen in the first 7 days of life. There was a positive correlation between logFT4 and logTSH (rs (1216) = 0.189, p = < 0.001). We derived TSH RIs for the age groups 2–4 days (0.403–7.942 µIU/mL) and 5–7 days (0.418–6.319 µIU/mL), and sex specific RIs for males (0.609–7.557 µIU/mL) and females (0.420–6.189 µIU/mL) aged 8–30 days. For FT4, separate RIs were derived for the age groups 2–4 days (1.19–2.59 ng/dL), 5–7 days (1.21–2.29 ng/dL) and 8–30 days (1.02–2.01 ng/dL).ConclusionOur neonatal RIs for TSH and FT4 are different from those published or recommended by Siemens. The RIs will serve as a guide for the interpretation of thyroid function tests in neonates from sub-Saharan Africa where routine screening for congenital hypothyroidism using serum samples is done on the Siemens Atellica® IM analyzer.

Reference Intervals for Thyroid Hormones and Thyroid Volume in Children Aged 7 ~ 13 Years from Iodine-Sufficient Areas in Tianjin, China.

Reference intervals (RIs) for serum thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), and free thyroxine (FT4) suitable for local children are urgently needed in northern China. The reference interval for thyroid volume (Tvol) in Chinese children also differed greatly from that recommended by the WHO. This study aimed to establish TSH, FT3, FT4, and Tvol RIs suitable for children in northern China. A total of 1070 children aged 7 ~ 13 were recruited from iodine nutrition-sufficient areas in Tianjin, China, from 2016 to 2021. Four hundred fifty-eight children aged 7 ~ 13years, and 815 children aged 8 ~ 10years were eventually included to study RIs for the thyroid hormones and Tvol. RIs for thyroid hormones were established in accordance with the Clinical Laboratory Standards Institute (CLSI) document C28-A3 guidelines. Quantile regression was used to analyze the influencing factors of Tvol. RIs for TSH, FT3, and FT4 were 1.23 (1.14 ~ 1.32) to 6.18 (5.92 ~ 7.26) mIU/L, 5.43 (5.29 ~ 5.52) to 7.89 (7.66 ~ 7.98) pmol/L, and 13.09 (12.85 ~ 13.73) to 22.22 (21.61 ~ 22.51) pmol/L. There was no need to establish RIs by age and gender. Our RIs could increase the prevalence of subclinical hyperthyroidism (P < 0.001) and reduce the prevalence of subclinical hypothyroidism (P < 0.001). Body surface area (BSA) and age are correlated with the 97th percentile of Tvol (both P < 0.001). Our reference interval could increase the goiter rate in children from 2.97 to 4.96% (P = 0.007). The thyroid hormones' reference intervals suitable for local children should be established. In addition, BSA and age should be considered when establishing Tvol reference interval.

Indirect Estimation of the Pediatric Reference Intervals for Thyroid Function Tests in Public Health Laboratory.

Reference intervals (RI) are an essential section of the information that medical laboratories present to clinicians to facilitate the management process of the patient. Thyroid-stimulating hormone (TSH), free thyroxine (fT4), and free triiodothyronine (fT3) are the most valuable and cost-effective parameters of thyroid functions. According to the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC), Clinical and Laboratory Standards Institute (CLSI), and American Thyroid Association (ATA), every laboratory should determine own RI on own population and method. In this study we aim to evaluate the pediatric reference intervals in a public health laboratory. The results of TSH, fT4, and fT3 from pediatric patients (aged: 0 - 18 years) were included in our study. These results were stored in our laboratory information system. TSH, fT4, and fT3 are measured in Abbott Architect i2000 (Abbott Diagnostics, Abbott Park, IL, USA) chemiluminescent microparticle immunoassay analyzer. RI study was conducted according to CLSI EP28-A3 guidelines. Results were evaluated with MedCalc ver. 19.2.1 (MedCalc Software Ltd., Ostend, Belgium), and Minitab 19.2 (Minitab Statistical Software, AppOnFly Inc., San Fransisco, CA, USA). The final study included 483 samples. Study sample consisted of 288 girls and 195 boys. Our reference intervals for TSH, fT4 and fT3 were found as 0.74 - 4.11 mIU/L, 0.80 - 1.42 ng/dL, and 2.40 - 4.38 pg/mL, respectively. Reference intervals were compatible with expected values in the insert sheets, except for fT3. Laboratories should implement their reference intervals based on CLSI C28-A3 guidelines.

Reference intervals for thyroid hormones for the elderly population and their influence on the diagnosis of subclinical hypothyroidism.

This study aims to establish reference intervals (RIs) for thyroid hormones in the elderly population and analyze their influence on the prevalence of subclinical hypothyroidism. Thyroid hormone records of subjects who underwent routine health checkup at our hospital between 2018 and 2020 were analyzed. Thyroid stimulating hormone (TSH), total triiodothyronine, total thyroxine, free triiodothyronine (FT3), and free thyroxine (FT4) levels were compared between young and elderly subjects. Thresholds of these thyroid hormones were established for elderly subjects. A total of 22,207 subjects were included. Of them, 2,254 (10.15%) were aged ≥ 65 years. Elderly subjects had higher TSH, and lower FT3 and FT4 levels when compared with young subjects. In the elderly group, the RIs for TSH, FT3 and FT4 were 0.55-5.14 mIU/L, 3.68-5.47 pmol/L, and 12.00-19.87 pmol/L, respectively. The age and sex specific RIs for TSH were 0.56-5.07 mIU/L for men and 0.51-5.25 mIU/L for women. With whole-group RIs and age and sex-specific RIs for elderly people, the prevalence of subclinical hypothyroidism was 9.83% and 6.29% (p < 0.001), respectively. Elderly individuals had higher TSH levels than young individuals. Our study indicated that establishing specific RIs for elderly individuals is needed. This has implications for the diagnosis and management of subclinical hypothyroidism in the elderly population.

Laboratory policies and practices for thyroid function tests in Croatia: survey on behalf of Working Group for Laboratory Endocrinology of the Croatian Society of Medical Biochemistry and Laboratory Medicine.

IntroductionLaboratory plays important part in screening, diagnosis, and management of thyroid disorders. The aim of this study was to estimate current laboratory preanalytical, analytical and postanalytical practices and policies in Croatia.Materials and methodsWorking Group for Laboratory Endocrinology of the Croatian Society of Medical Biochemistry and Laboratory Medicine designed a questionnaire with 27 questions and statements regarding practices and protocols in measuring thyroid function tests. The survey was sent to 111 medical biochemistry laboratories participating in external quality assurance scheme for thyroid hormones organized by Croatian Centre for Quality Assessment in Laboratory Medicine. Data is presented as absolute numbers and proportions.ResultsFifty-three participants returned the questionnaire. Response rate varied depending on question, yielding a total survey response rate of 46-48%. All respondents perform thyroid stimulating hormone (TSH). From all other thyroid tests, most performed is free thyroxine (37/53) and least TSH-stimulating immunoglobulin (1/53). Laboratories are using nine different immunoassay methods. One tenth of laboratories is verifying manufacturer’s declared limit of quantification for TSH and one third is verifying implemented reference intervals for all performed tests. Most of laboratories (91%) adopt the manufacturer’s reference interval for adult population. Reference intervals for TSH are reported with different percentiles (90, 95 or 99 percentiles).ConclusionThis survey showed current practices and policies in Croatian laboratories regarding thyroid testing. The results identified some critical spots and will serve as a foundation in creating national guidelines in order to harmonize laboratory procedures in thyroid testing in Croatia.

Adult and neonate TSH blood spot reference intervals.

Background: Neonatal congenital hypothyroidism screening is performed by measuring thyroid-stimulating hormone (TSH) in a dried blood spot (DBS) sample, whereas acquired hypothyroidism uses serum TSH. There is no established DBS TSH reference interval, but knowing this is useful, as some patients cannot tolerate venepuncture, so DBS collection is seen as an acceptable alternative. The aim of this study was to establish DBS TSH reference intervals in adults and neonates (day 5-8), and determine the relationship between serum and DBS TSH.Methods: Euthyroid adults, not on thyroid medication and with a normal haematocrit, were selected. If they had a paired lithium heparin sample, DBS were prepared by spotting 50µL of whole blood onto filter paper. Dried blood spot TSH was measured using the PerkinElmer Neonatal hTSH kit on the GSP instrument and serum using the Abbott Architect assay. The relationship between DBS and serum TSH was analysed using Passing-Bablok regression and the adult DBS TSH reference interval calculated using transformed data. The neonatal reference interval was calculated from screening results using the non-parametric method.Results: Overall, 109 adult samples were included in the study (61 female). The Passing-Bablok regression was: DBS TSH = 0.68 × serum TSH + 0.07, and reference interval was 0.49-3.07 mU/L. The neonatal DBS reference interval was 0.40-4.10 mU/L from 8351 results.Conclusion: This study derived adult and neonate TSH DBS reference intervals using the GSP analyser and established the relationship between serum and DBS TSH. Knowing this information will allow for improved interpretation of DBS TSH results.