Mendelian randomization supports a causative effect of TSH on thyroid carcinoma

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Abstract

Evidence from observational studies suggest a positive association between serum thyroid-stimulating hormone (TSH) levels and differentiated thyroid carcinoma. However, the cause–effect relationship is poorly understood and these studies are susceptible to bias and confounding. This study aimed to investigate the causal role of TSH in both benign thyroid nodules and thyroid cancer in up to 451,025 UK Biobank participants, using a genetic technique, known as Mendelian randomization (MR). Hospital Episode Statistics and Cancer Registry databases were used to identify 462 patients with differentiated thyroid carcinoma and 2031 patients with benign nodular thyroid disease. MR methods using genetic variants associated with serum TSH were used to test causal relationships between TSH and the two disease outcomes. Mendelian randomization provided evidence of a causal link between TSH and both thyroid cancer and benign nodular thyroid disease. Two-sample MR suggested that a 1 s.d. higher genetically instrumented TSH (approximately 0.8 mIU/L) resulted in 4.96-fold higher odds of benign nodular disease (95% CI 2.46–9.99) and 2.00-fold higher odds of thyroid cancer (95% CI 1.09–3.70). Our results thus support a causal role for TSH in both benign nodular thyroid disease and thyroid cancer.

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Assessing the suitability of summary data for two-sample Mendelian randomization analyses using MR-Egger regression: the role of the I2 statistic

Jack Bowden, Fabiola Del Greco M., Cosetta Minell … (2017)

Background MR-Egger regression has recently been proposed as a method for Mendelian randomization (MR) analyses incorporating summary data estimates of causal effect from multiple individual variants, which is robust to invalid instruments. It can be used to test for directional pleiotropy and provides an estimate of the causal effect adjusted for its presence. MR-Egger regression provides a useful additional sensitivity analysis to the standard inverse variance weighted (IVW) approach that assumes all variants are valid instruments. Both methods use weights that consider the single nucleotide polymorphism (SNP)-exposure associations to be known, rather than estimated. We call this the `NO Measurement Error’ (NOME) assumption. Causal effect estimates from the IVW approach exhibit weak instrument bias whenever the genetic variants utilized violate the NOME assumption, which can be reliably measured using the F-statistic. The effect of NOME violation on MR-Egger regression has yet to be studied. Methods An adaptation of the I 2 statistic from the field of meta-analysis is proposed to quantify the strength of NOME violation for MR-Egger. It lies between 0 and 1, and indicates the expected relative bias (or dilution) of the MR-Egger causal estimate in the two-sample MR context. We call it I G X 2 . The method of simulation extrapolation is also explored to counteract the dilution. Their joint utility is evaluated using simulated data and applied to a real MR example. Results In simulated two-sample MR analyses we show that, when a causal effect exists, the MR-Egger estimate of causal effect is biased towards the null when NOME is violated, and the stronger the violation (as indicated by lower values of I G X 2 ), the stronger the dilution. When additionally all genetic variants are valid instruments, the type I error rate of the MR-Egger test for pleiotropy is inflated and the causal effect underestimated. Simulation extrapolation is shown to substantially mitigate these adverse effects. We demonstrate our proposed approach for a two-sample summary data MR analysis to estimate the causal effect of low-density lipoprotein on heart disease risk. A high value of I G X 2 close to 1 indicates that dilution does not materially affect the standard MR-Egger analyses for these data. Conclusions Care must be taken to assess the NOME assumption via the I G X 2 statistic before implementing standard MR-Egger regression in the two-sample summary data context. If I G X 2 is sufficiently low (less than 90%), inferences from the method should be interpreted with caution and adjustment methods considered.

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The Bethesda System for Reporting Thyroid Cytopathology: a meta-analysis.

Massimo Bongiovanni, Alessandra Spitale, William Faquin … (2012)

We aimed to investigate the validity of the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) through meta-analysis. All publications between January 1, 2008 and September 1, 2011 that studied TBSRTC and had available histological follow-up data were retrieved. To calculate the sensitivity, specificity and diagnostic accuracy, the cases diagnosed as follicular neoplasm, suspicious for malignancy and malignant which were histopathologically confirmed as malignant were defined as true-positive. True-negative included benign cases confirmed as benign on histopathology. The nondiagnostic category was excluded from the statistical calculation. The correlations between the 6 diagnostic categories were investigated. The publications review resulted in a case cohort of 25,445 thyroid fine-needle aspirations, 6,362 (25%) of which underwent surgical excision; this group constituted the basis of the study. The sensitivity, specificity and diagnostic accuracy were 97, 50.7 and 68.8%, respectively. The positive predictive value and negative predictive value were 55.9 and 96.3%, respectively. The rates of false negatives and false positives were low: 3 and 0.5%, respectively. The results of meta-analysis showed high overall accuracy, indicating that TBSRTC represents a reliable and valid reporting system for thyroid cytology. Copyright © 2012 S. Karger AG, Basel.

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Higher serum thyroid stimulating hormone level in thyroid nodule patients is associated with greater risks of differentiated thyroid cancer and advanced tumor stage.

Glen Leverson, Juan Carlos Jaume, Herbert Chen … (2008)

TSH is a known thyroid growth factor, but the pathogenic role of TSH in thyroid oncogenesis is unclear. The aim was to examine the relationship between preoperative TSH and differentiated thyroid cancer (DTC). The design was a retrospective cohort. Between May 1994 and January 2007, 1198 patients underwent thyroid surgery at a single hospital. Data from the 843 patients with preoperative serum TSH concentration were recorded. Serum TSH concentration was measured with a sensitive assay. Diagnoses of DTC vs. benign thyroid disease were based on surgical pathology reports. Twenty-nine percent of patients (241 of 843) had DTC on final pathology. On both univariate and multivariable analyses, risk of malignancy correlated with higher TSH level (P=0.007). The likelihood of malignancy was 16% (nine of 55) when TSH was less than 0.06 mIU/liter vs. 52% (15 of 29) when 5.00 mIU/liter or greater (P=0.001). When TSH was between 0.40 and 1.39 mIU/liter, the likelihood of malignancy was 25% (85 of 347) vs. 35% (109 of 308) when TSH was between 1.40 and 4.99 mIU/liter (P=0.002). The mean TSH was 4.9+/-1.5 mIU/liter in patients with stage III/IV disease vs. 2.1+/-0.2 mIU/liter in patients with stage I/II disease (P=0.002). The likelihood of thyroid cancer increases with higher serum TSH concentration. Even within normal TSH ranges, a TSH level above the population mean is associated with significantly greater likelihood of thyroid cancer than a TSH below the mean. Shown for the first time, higher TSH level is associated with advanced stage DTC.

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Journal

Journal ID (nlm-ta): Endocr Relat Cancer

Journal ID (iso-abbrev): Endocr. Relat. Cancer

Journal ID (hwp): ERC

Title: Endocrine-Related Cancer

Publisher: Bioscientifica Ltd (Bristol )

ISSN (Print): 1351-0088

ISSN (Electronic): 1479-6821

Publication date Collection: October 2020

Publication date (Electronic): 21 July 2020

Volume: 27

Issue: 10

Pages: 551-559

Affiliations

[1 ]Head and Neck Surgery , Royal Devon and Exeter Hospital, Exeter, UK

[2 ]Genetics of Complex Traits , Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK

[3 ]Endocrinology , Royal Devon and Exeter Hospital, Exeter, UK

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Correspondence should be addressed to J M Fussey: jfussey@ 123456doctors.org.uk

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Jonathan M Fussey http://orcid.org/0000-0001-9971-4334

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Publisher ID: ERC-20-0067

DOI: 10.1530/ERC-20-0067

PMC ID: 7497356

SO-VID: c695b80e-2456-4729-a64a-debb0481a56a

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This work is licensed under a Creative Commons Attribution 4.0 International License.

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Mendelian randomization supports a causative effect of TSH on thyroid carcinoma

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Most cited references 23

Assessing the suitability of summary data for two-sample Mendelian randomization analyses using MR-Egger regression: the role of the I2 statistic

The Bethesda System for Reporting Thyroid Cytopathology: a meta-analysis.

Higher serum thyroid stimulating hormone level in thyroid nodule patients is associated with greater risks of differentiated thyroid cancer and advanced tumor stage.

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