Inconsistency in ferritin reference intervals across laboratories: a major concern for clinical decision making.

OBJECTIVES: Iron deficiency anemia is a significant global health concern, diagnosed by measuring hemoglobin concentrations in combination with plasma ferritin concentration. This study investigated the variability in ferritin reference intervals among laboratories in the Netherlands and examined how this affects the identification of iron-related disorders. METHODS: Ferritin reference intervals from 52 Dutch ISO15189-certified medical laboratories were collected. Ferritin, hemoglobin and mean corpuscular volume data of non-anemic apparently healthy primary care patients, measured by four laboratory platforms (Beckman, Abbott, Siemens, and Roche), were collected (n=397,548). Median ferritin levels were determined per platform, stratified by sex and age. The proportion of ferritin measurements outside of the reference interval was calculated using the reference intervals from the 52 laboratories (using a total of n=1,093,442 ferritin measurements). Lastly, ferritin data from 3,699 patients as captured in general practitioner (GP) data from the PHARMO Data Network were used to assess the variation of abnormal ferritin measurements per GP. RESULTS: Median plasma ferritin concentrations were approximately four times higher in men and twice as high in postmenopausal women compared to premenopausal women. Moreover, there are substantial differences in the median plasma ferritin concentration between the four platforms. However, even among laboratories using the same platform, ferritin reference intervals differ widely. This leads to significant differences in the percentages of measurements classified as abnormal, with the percentage of ferritin measurements below the reference limit in premenopausal women ranging from 11 to 53 %, in postmenopausal women from 3 to 37 %, and in men from 2 to 19 %. The percentage of ferritin measurements above the reference limit in premenopausal women ranged from 0.2 to 11 %, in postmenopausal women from 3 to 36 % and in men from 7 to 32 %. CONCLUSIONS: The lack of harmonization in ferritin measurement and the disagreement in plasma ferritin reference intervals significantly impact the interpretation of the iron status of patients and thereby the number of iron disorder diagnoses made. Standardization or harmonization of the ferritin assays and establishing uniform reference intervals and medical decision limits are essential to reduce the substantial variability in clinical interpretations of ferritin results.

Age-Specific Reference Intervals for Thyroid-Stimulating Hormones and Free Thyroxine 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, and 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 to 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 were higher in early childhood and decreased toward adulthood. In adulthood, TSH URLs increased from 60 years in men, and from 50 years in women, while FT4 URLs increased from 70 years onward. 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 are less uniform regarding FT4 age-specific RIs and more research should be performed before implementing these in clinical practice.

A systematic review of subclinical hyperthyroidism guidelines: a remarkable range of recommendations.

Background: Subclinical thyroid diseases are often the subject of debate concerning their clinical significance, the appropriateness of diagnostic testing, and possible treatment. This systematic review addresses the variation in international guidelines for subclinical hyperthyroidism, focusing on diagnostic workup, treatment, and follow-up recommendations. Methods: Following the PRISMA guidelines, we searched PubMed, Embase, and guideline-specific databases and included clinical practice guidelines with recommendations on subclinical hyperthyroidism. Guideline recommendations were extracted, and quality assessment was performed using selected questions of the Appraisal of Guidelines for Research & Evaluation (AGREE) II instrument. Results: Of the 2624 records screened, 22 guidelines were included, which were published between 2007 and 2021. Guideline quality was generally intermediate to low. Diagnostic approaches differed substantially, particularly in the extent of recommended testing. Treatment initiation depended on TSH levels, age, and comorbidities, but the level of detail regarding defining precise comorbidities varied. Recommendations for monitoring intervals for follow-up ranged from 3 to 12 months. Conclusion: This review underscores the existing variability in (inter)national guidelines concerning subclinical hyperthyroidism. There isa need for clear recommendations in guidelines considering diagnostic workup, treatment, and follow-up of subclinical hyperthyroidism. In order to establish this, future research should focus on determining clear and evidence-based intervention thresholds.

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.

OBJECTIVES: 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. METHODS: 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 per laboratory per year and clustered per manufacturer (>1.000.000 data points per manufacturer). Direct RIs (DRIs) were established in 125 healthy individuals per platform. RESULTS: 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. CONCLUSIONS: These results underscore the importance of RI verification as manufacturer-provided RIs are often incorrect and RIs may not be robust. Indirect methods offer cost-effective alternatives for laboratory-specific or platform-specific verification of RIs.

Troponin testing in routine primary care: observations from a dynamic cohort study in the Amsterdam metropolitan area.

OBJECTIVES: Troponin testing is indicated in the diagnostic work-up of acute coronary syndrome (ACS) and incorporated in risk stratification pathways. This study aims to gain insights on the use, outcomes, and diagnostic accuracy of troponin testing in routine primary care; a setting that is understudied. METHODS: Routine data were used from the academic primary care network in the Amsterdam metropolitan area (968,433 patient records). The study population included adult patients who underwent high-sensitivity troponin I or T (hs-TnI/T) testing between 2011 and 2021. The primary outcome was the reported diagnosis and the secondary outcome was the diagnostic accuracy measured by death or ACS at 30 days. RESULTS: 3,184 patients underwent hs-troponin testing, either with hsTNT (n=2,333) or hsTNI (n=851). Median patients' age was 55 (44-65) years, and 62.3 % were female. Predominant symptoms were chest pain and dyspnea (56.7 %). Additional diagnostic laboratory tests were commonly performed (CRP: 47.7 %, natriuretic peptides: 25.6 %, d-dimer: 21.5 %). Most common diagnoses were musculoskeletal symptoms (21.6 %) and coronary heart disease (7.1 %; 1.1 % ACS). Troponin testing showed sensitivity and specificity of 77.8 % (60.9-89.9) and 94.3 % (93.5-95.1), respectively. Negative and positive predictive values were 99.7 (99.5-99.9) and 13.5 (11.1-16.4), and positive and negative likelihood ratios were 13.7 (10.9-17.1) and 0.24 (0.13-0.43). CONCLUSIONS: GPs occasionally use troponin testing in very low-risk patients, often as part of a multi-marker rule-out strategy. The diagnostic characteristics of troponin tests, while promising, warrant prospective validation and implementation to facilitate appropriate use.

Incidence and Determinants of Spontaneous Normalization of Subclinical Hypothyroidism in Older Adults.

CONTEXT: With age, the prevalence of subclinical hypothyroidism rises. However, incidence and determinants of spontaneous normalization remain largely unknown. OBJECTIVE: To investigate incidence and determinants of spontaneous normalization of TSH levels in older adults with subclinical hypothyroidism. DESIGN: Pooled data were used from the (1) pretrial population and (2) in-trial placebo group from 2 randomized, double-blind, placebo-controlled trials (Thyroid Hormone Replacement for Untreated Older Adults With Subclinical Hypothyroidism Trial and Institute for Evidence-Based Medicine in Old Age thyroid 80-plus thyroid trial). SETTING: Community-dwelling 65+ adults with subclinical hypothyroidism from the Netherlands, Switzerland, Ireland, and the United Kingdom. PARTICIPANTS: The pretrial population (N = 2335) consisted of older adults with biochemical subclinical hypothyroidism, defined as ≥1 elevated TSH measurement (≥4.60 mIU/L) and a free T4 within the laboratory-specific reference range. Individuals with persistent subclinical hypothyroidism, defined as ≥2 elevated TSH measurements ≥3 months apart, were randomized to levothyroxine/placebo, of which the in-trial placebo group (N = 361) was included. MAIN OUTCOME MEASURES: Incidence of spontaneous normalization of TSH levels and associations between participant characteristics and normalization. RESULTS: In the pretrial phase, TSH levels normalized in 60.8% of participants in a median follow-up of 1 year. In the in-trial phase, levels normalized in 39.9% of participants after 1 year of follow-up. Younger age, female sex, lower initial TSH level, higher initial free T4 level, absence of thyroid peroxidase antibodies, and a follow-up measurement in summer were independent determinants for normalization. CONCLUSION: Because TSH levels spontaneously normalized in a large proportion of older adults with subclinical hypothyroidism (also after confirmation by repeat measurement), a third measurement may be recommended before considering treatment. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01660126 and Netherlands Trial Register, NTR3851.

The impact of the COVID-19 pandemic on Positive Health among older adults in relation to the complexity of health problems.

BACKGROUND: The broad concept of health as "the ability to adapt and self-manage in the face of social, physical and emotional challenges" has been operationalized by "Positive Health," a framework increasingly used in the Netherlands. We explored to what degree the impact of the COVID-19 pandemic and preventive measures on Positive Health differed between community-dwelling older adults without, with mild and with complex health problems, as well as differences flowing from their use of preventive measures. METHODS: During the second wave in the Netherlands (November 2020-February 2021), a convenience sample of adults aged ≥65 years completed an online questionnaire. Positive Health impact was measured based on self-reported change of current health status, across six dimensions, compared to before the pandemic (decreased/unchanged/increased). The complexity of health problems (past month) was assessed using the validated ISCOPE tool, comparing subgroups without, with mild or with complex health problems. High use of preventive measures was defined as ≥9 of 13 measures and compared to low use (<9 measures). RESULTS: Of the 2397 participants (median age 71 years, 60% female, and 4% previous COVID-19 infection), 31% experienced no health problems, 55% mild health problems, and 15% complex health problems. Overall, participants reported a median decrease in one Positive Health dimension (IQR 1-3), most commonly in social participation (68%). With an increasing complexity of health problems, subjective Positive Health declined more often across all six dimensions, ranging from 3.3% to 57% in those without, from 22% to 72% in those with mild, and from 47% to 75% in those with complex health problems (p-values for trend <0.001; independent of age and sex). High users of preventive measures more often experienced declined social participation (72% vs. 62%, p < 0.001) and a declined quality of life (36% vs. 30%, p = 0.007) than low users, especially those with complex health problems. CONCLUSION: As the complexity of health problems increased, the adverse impact of the COVID-19 pandemic and related preventive measures was experienced more frequently across all dimensions of Positive Health. Acknowledging this heterogeneity is pivotal to the effective targeting of prevention and healthcare to those most in need.

The effect of hormonal contraceptive therapy on clinical laboratory parameters: a literature review.

Hormonal contraceptives (HC) are widely used among women in reproductive ages. In this review, the effects of HCs on 91 routine chemistry tests, metabolic tests, and tests for liver function, hemostatic system, renal function, hormones, vitamins and minerals were evaluated. Test parameters were differently affected by the dosage, duration, composition of HCs and route of administration. Most studies concerned the effects of combined oral contraceptives (COC) on the metabolic, hemostatic and (sex) steroids test results. Although the majority of the effects were minor, a major increase was seen in angiotensinogen levels (90-375 %) and the concentrations of the binding proteins (SHBG [∼200 %], CBG [∼100 %], TBG [∼90 %], VDBP [∼30 %], and IGFBPs [∼40 %]). Also, there were significant changes in levels of their bound molecules (testosterone, T3, T4, cortisol, vitamin D, IGF1 and GH). Data about the effects of all kinds of HCs on all test results are limited and sometimes inconclusive due to the large variety in HC, administration routes and dosages. Still, it can be concluded that HC use in women mainly stimulates the liver production of binding proteins. All biochemical test results of women using HC should be assessed carefully and unexpected test results should be further evaluated for both methodological and pre-analytical reasons. As HCs change over time, future studies are needed to learn more about the effects of other types, routes and combinations of HCs on clinical chemistry tests.

Optimizing the Dutch newborn screening for congenital hypothyroidism by incorporating amino acids and acylcarnitines in a machine learning-based model.

Objective: Congenital hypothyroidism (CH) is an inborn thyroid hormone (TH) deficiency mostly caused by thyroidal (primary CH) or hypothalamic/pituitary (central CH) disturbances. Most CH newborn screening (NBS) programs are thyroid-stimulating-hormone (TSH) based, thereby only detecting primary CH. The Dutch NBS is based on measuring total thyroxine (T4) from dried blood spots, aiming to detect primary and central CH at the cost of more false-positive referrals (FPRs) (positive predictive value (PPV) of 21% in 2007-2017). An artificial PPV of 26% was yielded when using a machine learning-based model on the adjusted dataset described based on the Dutch CH NBS. Recently, amino acids (AAs) and acylcarnitines (ACs) have been shown to be associated with TH concentration. We therefore aimed to investigate whether AAs and ACs measured during NBS can contribute to better performance of the CH screening in the Netherlands by using a revised machine learning-based model. Methods: Dutch NBS data between 2007 and 2017 (CH screening results, AAs and ACs) from 1079 FPRs, 515 newborns with primary (431) and central CH (84) and data from 1842 healthy controls were used. A random forest model including these data was developed. Results: The random forest model with an artificial sensitivity of 100% yielded a PPV of 48% and AUROC of 0.99. Besides T4 and TSH, tyrosine, and succinylacetone were the main parameters contributing to the model's performance. Conclusions: The PPV improved significantly (26-48%) by adding several AAs and ACs to our machine learning-based model, suggesting that adding these parameters benefits the current algorithm.

How low can we (reliably) go? A method comparison of thyroid-stimulating hormone assays with a focus on low concentrations.

Objective: International guidelines concerning subclinical hyperthyroidism and thyroid cancer advice absolute cut-off values for aiding clinical decisions in the low range of thyroid-stimulating hormone (TSH) concentrations. As TSH assays are known to be poorly standardized in the normal to high range, we performed a TSH assay method comparison focusing on the low range. Methods: Sixty samples, selected to cover a wide range of TSH concentrations (<0.01 to 120 mIU/L) with oversampling in the lower range (<0.4 mIU/L), were used for the method comparison between three TSH immunoassays (Cobas, Alinity and Atellica). In addition, 20 samples were used to assess the coefficient of variation from duplicate measurements in these three methods. Results: The TSH immunoassays showed standardization differences with a bias of 7-16% for the total range and 1-14% for the low range. This could lead to a different classification of 1.5% of all measured TSH concentrations <0.40 mIU/L measured in our laboratory over the last 6 months, regarding the clinically important cut-off value of TSH = 0.1 mIU/L. As the imprecision of the immunoassays varied from 1.6-5.5%, this could lead to a similar reclassification as the bias between immunoassays. Conclusions: We established the standardization differences of frequently used TSH assays for the total and low concentration ranges. Based on the proportional bias and the imprecision, this effect seems to have limited clinical consequences for the low TSH concentration range. Nevertheless, as guidelines mention absolute TSH values to guide clinical decision-making, caution must be applied when interpreting values close to these cut-offs.

Harmonization of indirect reference intervals calculation by the Bhattacharya method.

OBJECTIVES: The aim of this study was to harmonize the criteria for the Bhattacharya indirect method Microsoft Excel Spreadsheet for reference intervals calculation to reduce between-user variability and use these criteria to calculate and evaluate reference intervals for eight analytes in two different years. METHODS: Anonymized laboratory test results from outpatients were extracted from January 1st 2018 to December 31st 2019. To assure data quality, we examined the monthly results from an external quality control program. Reference intervals were determined by the Bhattacharya method with the St Vincent's hospital Spreadsheet firstly using original criteria and then using additional harmonized criteria defined in this study. Consensus reference intervals using the additional harmonized criteria were calculated as the mean of four users' lower and upper reference interval results. To further test the operation criteria and robustness of the obtained reference intervals, an external user validated the Spreadsheet procedure. RESULTS: The extracted test results for all selected laboratory tests fulfilled the quality criteria and were included in the present study. Differences between users in calculated reference intervals were frequent when using the Spreadsheet. Therefore, additional criteria for the Spreadsheet were proposed and applied by independent users, such as: to set central bin as the mean of all the data, bin size as small as possible, at least three consecutive bins and a high proportion of bins within the curve. CONCLUSIONS: The proposed criteria contributed to the harmonization of reference interval calculation between users of the Bhattacharya indirect method Spreadsheet.

Moving average quality control of routine chemistry and hematology parameters - a toolbox for implementation.

OBJECTIVES: Moving average quality control (MA QC) is a patient-based real-time quality control system. Advantages compared to conventional periodic internal quality control (IQC) include absence of commutability problems and continuous monitoring of performance. We implemented MA QC for multiple routine hematology and chemistry parameters. We describe the evaluation process and provide practical tools to aid MA QC implementation. METHODS: Nine parameters (serum sodium, calcium, bicarbonate and free thyroxine, hemoglobin [Hb], mean corpuscular volume, mean corpuscular hemoglobin concentration [MCHC], reticulocyte count and erythrocyte sedimentation rate [ESR]) were chosen for initial consideration. Using data extractions from the laboratory information system (LIS; General Laboratory Information Management System), evaluation of usefulness and optimization of MA QC settings was performed using bias detection curves. After this, MA QC settings were incorporated in our LIS for further evaluation and implementation in routine care. RESULTS: Three out of nine parameters (Hb, ESR, and sodium) were excluded from MA QC implementation due to high variation and technical issues in the LIS. For the six remaining parameters, MA QC showed added value to IQC and was therefore implemented in the LIS. For three parameters a direct MA alarm work-up method was set up, including newly developed built-in features in the LIS. For the other parameters, we identified MA utilization beyond real-time monitoring. CONCLUSIONS: Implementation of MA QC has added value for our laboratory setting. Additional utilization beyond real-time QC monitoring was identified. We find MA QC especially useful for trend monitoring, detection of small shifts after maintenance and inter-analyzer comparisons.

Thyroid antibodies and levothyroxine effects in subclinical hypothyroidism: A pooled analysis of two randomized controlled trials.

BACKGROUND: Antithyroid antibodies increase the likelihood of developing overt hypothyroidism, but their clinical utility remains unclear. No large randomized controlled trial (RCT) has assessed whether older adults with subclinical hypothyroidism (SHypo) caused by autoimmune thyroid disease derive more benefits from levothyroxine treatment (LT4). OBJECTIVE: To determine whether older adults with SHypo and positive antibodies derive more clinical benefits from LT4 than those with negative antibodies. METHODS: We pooled individual participant data from two RCTs, Thyroid Hormone Replacement for Untreated Older Adults with Subclinical Hypothyroidism and IEMO 80+. Participants with persistent SHypo were randomly assigned to receive LT4 or placebo. We compared the effects of LT4 versus placebo in participants with and without anti-thyroid peroxidase (TPO) at baseline. The two primary outcomes were 1-year change in Hypothyroid Symptoms and Tiredness scores on the Thyroid-Related Quality-of-Life Patient-Reported Outcome Questionnaire. RESULTS: Among 660 participants (54% women) ≥65 years, 188 (28.5%) had positive anti-TPO. LT4 versus placebo on Hypothyroid Symptoms lead to an adjusted between-group difference of -2.07 (95% confidence interval: -6.04 to 1.90) for positive antibodies versus 0.89 (-1.76 to 3.54) for negative antibodies (p for interaction = 0.31). Similarly, there was no treatment effect modification by baseline antibody status for Tiredness scores-adjusted between-group difference 1.75 (-3.60 to 7.09) for positive antibodies versus 1.14 (-1.90 to 4.19) for negative antibodies (p for interaction = 0.98). Positive anti-TPO were not associated with better quality of life, improvement in handgrip strength, or fewer cardiovascular outcomes with levothyroxine treatment. CONCLUSIONS: Among older adults with SHypo, positive antithyroid antibodies are not associated with more benefits on clinical outcomes with LT4.

Indirect determination of biochemistry reference intervals using outpatient data.

The aim of this study was to determine reference intervals in an outpatient population from Vall d'Hebron laboratory using an indirect approach previously described in a Dutch population (NUMBER project). We used anonymized test results from individuals visiting general practitioners and analysed during 2018. Analytical quality was assured by EQA performance, daily average monitoring and by assessing longitudinal accuracy between 2018 and 2020 (using trueness verifiers from Dutch EQA). Per test, outliers by biochemically related tests were excluded, data were transformed to a normal distribution (if necessary) and means and standard deviations were calculated, stratified by age and sex. In addition, the reference limit estimator method was also used to calculate reference intervals using the same dataset. Finally, for standardized tests reference intervals obtained were compared with the published NUMBER results. Reference intervals were calculated using data from 509,408 clinical requests. For biochemical tests following a normal distribution, similar reference intervals were found between Vall d'Hebron and the Dutch study. For creatinine and urea, reference intervals increased with age in both populations. The upper limits of Gamma-glutamyl transferase were markedly higher in the Dutch study compared to Vall d'Hebron results. Creatine kinase and uric acid reference intervals were higher in both populations compared to conventional reference intervals. Medical test results following a normal distribution showed comparable and consistent reference intervals between studies. Therefore a simple indirect method is a feasible and cost-efficient approach for calculating reference intervals. Yet, for generating standardized calculated reference intervals that are traceable to higher order materials and methods, efforts should also focus on test standardization and bias assessment using commutable trueness verifiers.

Incorporating Baseline Outcome Data in Individual Participant Data Meta-Analysis of Non-randomized Studies.

Background: In non-randomized studies (NRSs) where a continuous outcome variable (e.g., depressive symptoms) is assessed at baseline and follow-up, it is common to observe imbalance of the baseline values between the treatment/exposure group and control group. This may bias the study and consequently a meta-analysis (MA) estimate. These estimates may differ across statistical methods used to deal with this issue. Analysis of individual participant data (IPD) allows standardization of methods across studies. We aimed to identify methods used in published IPD-MAs of NRSs for continuous outcomes, and to compare different methods to account for baseline values of outcome variables in IPD-MA of NRSs using two empirical examples from the Thyroid Studies Collaboration (TSC). Methods: For the first aim we systematically searched in MEDLINE, EMBASE, and Cochrane from inception to February 2021 to identify published IPD-MAs of NRSs that adjusted for baseline outcome measures in the analysis of continuous outcomes. For the second aim, we applied analysis of covariance (ANCOVA), change score, propensity score and the naïve approach (ignores the baseline outcome data) in IPD-MA from NRSs on the association between subclinical hyperthyroidism and depressive symptoms and renal function. We estimated the study and meta-analytic mean difference (MD) and relative standard error (SE). We used both fixed- and random-effects MA. Results: Ten of 18 (56%) of the included studies used the change score method, seven (39%) studies used ANCOVA and one the propensity score (5%). The study estimates were similar across the methods in studies in which groups were balanced at baseline with regard to outcome variables but differed in studies with baseline imbalance. In our empirical examples, ANCOVA and change score showed study results on the same direction, not the propensity score. In our applications, ANCOVA provided more precise estimates, both at study and meta-analytical level, in comparison to other methods. Heterogeneity was higher when change score was used as outcome, moderate for ANCOVA and null with the propensity score. Conclusion: ANCOVA provided the most precise estimates at both study and meta-analytic level and thus seems preferable in the meta-analysis of IPD from non-randomized studies. For the studies that were well-balanced between groups, change score, and ANCOVA performed similarly.

No Effect of Levothyroxine on Hemoglobin in Older Adults With Subclinical Hypothyroidism: Pooled Results From 2 Randomized Controlled Trials.

CONTEXT: Subclinical thyroid dysfunction and anemia are common disorders, and both have increasing prevalence with advancing age. OBJECTIVE: The aim of this study was to assess whether levothyroxine treatment leads to a rise in hemoglobin levels in older persons with subclinical hypothyroidism. METHODS: This preplanned combined analysis of 2 randomized controlled trials included community-dwelling persons aged 65 years and older with subclinical hypothyroidism who were randomly assigned to levothyroxine or placebo treatment. The levothyroxine dose was periodically titrated aiming at thyroid stimulating hormone (TSH) level within the reference range, with mock titrations in the placebo group. The main outcome measure was the change in hemoglobin level after 12 months. RESULTS: Analyses included 669 participants (placebo n = 337, levothyroxine n = 332) with a median age of 75 years (range, 65-97) and mean baseline hemoglobin of 13.8 ±â€…1.3 g/dL. Although levothyroxine treatment resulted in a reduction in TSH from baseline after 12 months of follow-up compared with placebo, the change in hemoglobin level was not different between the levothyroxine and the placebo groups (-0.03 g/dL [95% CI, -0.16 to 0.11]). Similar results were found in stratified analyses including sex, age, or TSH levels. No difference in change of hemoglobin levels after 12 months was identified in 69 participants with anemia at baseline (-0.33 g/dL [95% CI, -0.87 to 0.21]). CONCLUSION: In persons aged 65 years and older with subclinical hypothyroidism, treatment with levothyroxine does not lead to a rise in hemoglobin levels, regardless of the presence of anemia.

Thyroid Function and Risk of Anemia: A Multivariable-Adjusted and Mendelian Randomization Analysis in the UK Biobank.

CONTEXT: Thyroid dysfunction is associated with higher anemia prevalence, although causality remains unclear. OBJECTIVE: This study aimed to investigate the association between thyroid function and anemia. METHODS: This cross-sectional and Mendelian randomization study included 445 482 European participants from the UK Biobank (mean age 56.77 years (SD 8.0); and 54.2% women). Self-reported clinical diagnosis of hypothyroidism was stated by 21 860 (4.9%); self-reported clinical diagnosis of hyperthyroidism by 3431 (0.8%). Anemia, defined as hemoglobin level of < 13 g/dL in men and < 12 g/dL in women, was present in 18 717 (4.2%) participants. RESULTS: In cross-sectional logistic regression analyses, self-reported clinical diagnoses of hypo- and hyperthyroidism were associated with higher odds of anemia (OR 1.12; 95% CI, 1.05-1.19 and OR 1.09; 95% CI, 0.91-1.30), although with wide confidence intervals for hyperthyroidism. We did not observe an association of higher or lower genetically influenced thyrotropin (TSH) with anemia (vs middle tertile: OR for lowest tertile 0.98 [95% CI, 0.95-1.02]; highest tertile 1.02 [95% CI, 0.98-1.06]), nor of genetically influenced free thyroxine (fT4) with anemia. Individuals with genetic variants in the DIO3OS gene implicated in intracellular regulation of thyroid hormones had a higher anemia risk (OR 1.05; 95% CI, 1.02-1.10); no association was observed with variants in DIO1 or DIO2 genes. CONCLUSION: While self-reported clinical diagnosis of hypothyroidism was associated with higher anemia risk, we did not find evidence supporting a causal association with variation of thyroid function within the euthyroid range. However, intracellular regulation of thyroid hormones might play a role in developing anemia.

Association of Thyroid Dysfunction With Cognitive Function: An Individual Participant Data Analysis.

Importance: In clinical guidelines, overt and subclinical thyroid dysfunction are mentioned as causal and treatable factors for cognitive decline. However, the scientific literature on these associations shows inconsistent findings. Objective: To assess cross-sectional and longitudinal associations of baseline thyroid dysfunction with cognitive function and dementia. Design, Setting, and Participants: This multicohort individual participant data analysis assessed 114 267 person-years (median, 1.7-11.3 years) of follow-up for cognitive function and 525 222 person-years (median, 3.8-15.3 years) for dementia between 1989 and 2017. Analyses on cognitive function included 21 cohorts comprising 38 144 participants. Analyses on dementia included eight cohorts with a total of 2033 cases with dementia and 44 573 controls. Data analysis was performed from December 2016 to January 2021. Exposures: Thyroid function was classified as overt hyperthyroidism, subclinical hyperthyroidism, euthyroidism, subclinical hypothyroidism, and overt hypothyroidism based on uniform thyrotropin cutoff values and study-specific free thyroxine values. Main Outcomes and Measures: The primary outcome was global cognitive function, mostly measured using the Mini-Mental State Examination. Executive function, memory, and dementia were secondary outcomes. Analyses were first performed at study level using multivariable linear regression and multivariable Cox regression, respectively. The studies were combined with restricted maximum likelihood meta-analysis. To overcome the use of different scales, results were transformed to standardized mean differences. For incident dementia, hazard ratios were calculated. Results: Among 74 565 total participants, 66 567 (89.3%) participants had normal thyroid function, 577 (0.8%) had overt hyperthyroidism, 2557 (3.4%) had subclinical hyperthyroidism, 4167 (5.6%) had subclinical hypothyroidism, and 697 (0.9%) had overt hypothyroidism. The study-specific median age at baseline varied from 57 to 93 years; 42 847 (57.5%) participants were women. Thyroid dysfunction was not associated with global cognitive function; the largest differences were observed between overt hypothyroidism and euthyroidism-cross-sectionally (-0.06 standardized mean difference in score; 95% CI, -0.20 to 0.08; P = .40) and longitudinally (0.11 standardized mean difference higher decline per year; 95% CI, -0.01 to 0.23; P = .09). No consistent associations were observed between thyroid dysfunction and executive function, memory, or risk of dementia. Conclusions and Relevance: In this individual participant data analysis of more than 74 000 adults, subclinical hypothyroidism and hyperthyroidism were not associated with cognitive function, cognitive decline, or incident dementia. No rigorous conclusions can be drawn regarding the role of overt thyroid dysfunction in risk of dementia. These findings do not support the practice of screening for subclinical thyroid dysfunction in the context of cognitive decline in older adults as recommended in current guidelines.

The effects of single and a combination of determinants of anaemia in the very old: results from the TULIPS consortium.

BACKGROUND AND OBJECTIVES: Nutritional deficiencies, renal impairment and chronic inflammation are commonly mentioned determinants of anaemia. The aim of this study was to investigate the effects of these determinants, singly and in combination, on anaemia in the very old. METHOD: The TULIPS Consortium consists of four population-based studies in oldest-old individuals: Leiden 85-plus Study, LiLACS NZ, Newcastle 85+ study, and TOOTH. Five selected determinants (iron, vitamin B12, and folate deficiency; low estimated glomerular filtration rate (eGFR); and high C-reactive protein (CRP)) were summed. This sum score was used to investigate the association with the presence and onset of anaemia (WHO definition). The individual study results were pooled using random-effects models. RESULTS: In the 2216 participants (59% female, 30% anaemia) at baseline, iron deficiency, low eGFR and high CRP were individually associated with the presence of anaemia. Low eGFR and high CRP were individually associated with the onset of anaemia. In the cross-sectional analyses, an increase per additional determinant (adjusted OR 2.10 (95% CI 1.85-2.38)) and a combination of ≥2 determinants (OR 3.44 (95% CI 2.70-4.38)) were associated with the presence of anaemia. In the prospective analyses, an increase per additional determinant (adjusted HR 1.46 (95% CI 1.24-1.71)) and the presence of ≥2 determinants (HR 1.95 (95% CI 1.40-2.71)) were associated with the onset of anaemia. CONCLUSION: Very old adults with a combination of determinants of anaemia have a higher risk of having, and of developing, anaemia. Further research is recommended to explore causality and clinical relevance.