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Rolf H H Groenwold and Olaf M Dekkers

The validity of clinical research is potentially threatened by missing data. Any variable measured in a study can have missing values, including the exposure, the outcome, and confounders. When missing values are ignored in the analysis, only those subjects with complete records will be included in the analysis. This may lead to biased results and loss of power. We explain why missing data may lead to bias and discuss a commonly used classification of missing data.

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Saskia le Cessie, Jelle J Goeman, and Olaf M Dekkers

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Herman Verloop, Olaf M Dekkers, Robin P Peeters, Jan W Schoones, and Johannes W A Smit

Iodothyronine deiodinases represent a family of selenoproteins involved in peripheral and local homeostasis of thyroid hormone action. Deiodinases are expressed in multiple organs and thyroid hormone affects numerous biological systems, thus genetic variation in deiodinases may affect multiple clinical endpoints. Interest in clinical effects of genetic variation in deiodinases has clearly increased. We aimed to provide an overview for the role of deiodinase polymorphisms in human physiology and morbidity. In this systematic review, studies evaluating the relationship between deiodinase polymorphisms and clinical parameters in humans were eligible. No restrictions on publication date were imposed. The following databases were searched up to August 2013: Pubmed, EMBASE (OVID-version), Web of Science, COCHRANE Library, CINAHL (EbscoHOST-version), Academic Search Premier (EbscoHOST-version), and ScienceDirect. Deiodinase physiology at molecular and tissue level is described, and finally the role of these polymorphisms in pathophysiological conditions is reviewed. Deiodinase type 1 (D1) polymorphisms particularly show moderate-to-strong relationships with thyroid hormone parameters, IGF1 production, and risk for depression. D2 variants correlate with thyroid hormone levels, insulin resistance, bipolar mood disorder, psychological well-being, mental retardation, hypertension, and risk for osteoarthritis. D3 polymorphisms showed no relationship with inter-individual variation in serum thyroid hormone parameters. One D3 polymorphism was associated with risk for osteoarthritis. Genetic deiodinase profiles only explain a small proportion of inter-individual variations in serum thyroid hormone levels. Evidence suggests a role of genetic deiodinase variants in certain pathophysiological conditions. The value for determination of deiodinase polymorphism in clinical practice needs further investigation.

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Saskia le Cessie, Jelle J Goeman, and Olaf M Dekkers

When statistically comparing outcomes between two groups, researchers have to decide whether to use parametric methods, such as the t-test, or non-parametric methods, like the Mann–Whitney test. In endocrinology, for example, many studies compare hormone levels between groups, or at different points in time. Many papers apply non-parametric tests to compare groups. We will explain that non-parametric tests have clear drawbacks in medical research, and, that’s the good news, they are often not necessary.

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Wiebke Arlt, Olaf M Dekkers, Juliane Léger, and Robert K Semple

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Philippe Chanson, Alexandre Dormoy, and Olaf M Dekkers

Surgery is the treatment of choice for non-functioning pituitary macroadenomas (NFPAs). In cases of postoperative remnant growth or tumor recurrence, radiotherapy (RT) can be considered. The role of RT in the postoperative management of NFPAs is still debated. The main arguments against routine use of RT are the lack of randomized controlled trials, the use of clinically irrelevant endpoints in most studies on RT, the benign character of the condition, the potential for side effects of RT, and the option to apply RT at a later stage. However, because of its excellent efficacy in inhibiting tumor growth, reducing tumor volume and improving any existing visual defects, and as its side effects seem to be limited compared to the benefits provided, RT keeps a place in the management of NFPAs when a tumor remnant persists, particularly if it is invasive and displays high proliferation markers, if surveillance shows a relevant increase in tumor volume or if the tumor is close to the optic chiasm. The size of the remnant, its vicinity with the optic pathways, and the potential risk to healthy surrounding tissues need to be considered when deciding on an RT procedure.

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Femke M van Haalen, Leonie H A Broersen, Jens O Jorgensen, Alberto M Pereira, and Olaf M Dekkers

The aim of this systematic review and meta-analysis was to investigate whether mortality is increased in patients biochemically cured after initial treatment for Cushing's disease. This is a systematic review and meta-analysis of follow-up studies in patients cured from Cushing's disease after initial treatment was performed. Eight electronic databases were searched from 1975 to March 2014 to identify potentially relevant articles. Original articles reporting the standardized mortality ratio (SMR) for patients cured of Cushing's disease were eligible for inclusion. SMRs were pooled in a random effects model. I 2 statistics was used for quantification of heterogeneity. Eight cohort studies with a total of 766 patients were included. Out of eight studies, seven showed an SMR above 1.0 for cured patients. The pooled SMR was 2.5 (95% CI 1.4–4.2). The I 2 statistics showed evidence for statistical heterogeneity (78%, Q-statistics P<0.001), which was largely explained by two outliers. This meta-analysis reveals that mortality remains increased in patients with Cushing's disease even after initial biochemical cure remission, suggesting that cure does not directly reverse the metabolic consequences of long-term overexposure to cortisol. Other conditions such as hypopituitarism, including persistent adrenocortical insufficiency after surgery, may also contribute to the increased mortality risk.

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Jens Bollerslev, Lars Rejnmark, Claudio Marcocci, Dolores M Shoback, Antonio Sitges-Serra, Wim van Biesen, and Olaf M Dekkers

Hypoparathyroidism (HypoPT) is a rare (orphan) endocrine disease with low calcium and inappropriately low (insufficient) circulating parathyroid hormone levels, most often in adults secondary to thyroid surgery. Standard treatment is activated vitamin D analogues and calcium supplementation and not replacement of the lacking hormone, as in other hormonal deficiency states. The purpose of this guideline is to provide clinicians with guidance on the treatment and monitoring of chronic HypoPT in adults who do not have end-stage renal disease. We intend to draft a practical guideline, focusing on operationalized recommendations deemed to be useful in the daily management of patients. This guideline was developed and solely sponsored by The European Society of Endocrinology, supported by CBO (Dutch Institute for Health Care Improvement) and based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) principles as a methodological base. The clinical question on which the systematic literature search was based and for which available evidence was synthesized was: what is the best treatment for adult patients with chronic HypoPT? This systematic search found 1100 articles, which was reduced to 312 based on title and abstract. The working group assessed these for eligibility in more detail, and 32 full-text articles were assessed. For the final recommendations, other literature was also taken into account. Little evidence is available on how best to treat HypoPT. Data on quality of life and the risk of complications have just started to emerge, and clinical trials on how to optimize therapy are essentially non-existent. Most studies are of limited sample size, hampering firm conclusions. No studies are available relating target calcium levels with clinically relevant endpoints. Hence it is not possible to formulate recommendations based on strict evidence. This guideline is therefore mainly based on how patients are managed in clinical practice, as reported in small case series and based on the experiences of the authors.

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Mette Søgaard, Dóra Körmendiné Farkas, Vera Ehrenstein, Jens Otto Lunde Jørgensen, Olaf M Dekkers, and Henrik Toft Sørensen

Objective

The association between thyroid disease and breast cancer risk remains unclear. We, therefore examined the association between hypothyroidism, hyperthyroidism and breast cancer risk.

Design

This was a population-based cohort study.

Methods

Using nationwide registries, we identified all women in Denmark with a first-time hospital diagnosis of hypothyroidism or hyperthyroidism, 1978–2013. We estimated the excess risk of breast cancer among patients with hypothyroidism or hyperthyroidism compared with the expected risk in the general population, using standardized incidence ratios (SIRs) as a measure of risk ratio. Breast cancer diagnoses in the first 12 months following diagnosis of thyroid disease were excluded from the calculations to avoid diagnostic work-up bias.

Results

We included 61 873 women diagnosed with hypothyroidism and 80 343 women diagnosed with hyperthyroidism. Median follow-up time was 4.9 years (interquartile range (IQR): 1.8–9.5 years) for hypothyroidism and 7.4 years (IQR: 3.1–13.5 years) for hyperthyroidism. Hyperthyroidism was associated with a slightly increased breast cancer risk compared with the general population (SIR: 1.11, 95% CI: 1.07–1.16), which persisted beyond 5 years of follow-up (SIR: 1.13, 95% CI: 1.08–1.19). In comparison, hypothyroidism was associated with a slightly lower risk of breast cancer (SIR: 0.94, 95% CI: 0.88–1.00). Stratification by cancer stage at diagnosis, estrogen receptor status, age, comorbidity, history of alcohol-related disease and clinical diagnoses of obesity produced little change in cancer risk.

Conclusions

We found an increased risk of breast cancer in women with hyperthyroidism and a slightly decreased risk in women with hypothyroidism indicating an association between thyroid function level and breast cancer risk.

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Olaf M Dekkers, Erzsébet Horváth-Puhó, Suzanne C Cannegieter, Jan P Vandenbroucke, Henrik Toft Sørensen, and Jens Otto L Jørgensen

Objective

Several studies have shown an increased risk for cardiovascular disease (CVD) in hyperthyroidism, but most studies have been too small to address the effect of hyperthyroidism on individual cardiovascular endpoints. Our main aim was to assess the association among hyperthyroidism, acute cardiovascular events and mortality.

Design

It is a nationwide population-based cohort study. Data were obtained from the Danish Civil Registration System and the Danish National Patient Registry, which covers all Danish hospitals. We compared the rate of all-cause mortality as well as venous thromboembolism (VTE), acute myocardial infarction (AMI), ischemic and non-ischemic stroke, arterial embolism, atrial fibrillation (AF) and percutaneous coronary intervention (PCI) in the two cohorts. Hazard ratios (HR) with 95% confidence intervals (95% CI) were estimated.

Results

The study included 85 856 hyperthyroid patients and 847 057 matched population-based controls. Mean follow-up time was 9.2 years. The HR for mortality was highest in the first 3 months after diagnosis of hyperthyroidism: 4.62, 95% CI: 4.40–4.85, and remained elevated during long-term follow-up (>3 years) (HR: 1.35, 95% CI: 1.33–1.37). The risk for all examined cardiovascular events was increased, with the highest risk in the first 3 months after hyperthyroidism diagnosis. The 3-month post-diagnosis risk was highest for atrial fibrillation (HR: 7.32, 95% CI: 6.58–8.14) and arterial embolism (HR: 6.08, 95% CI: 4.30–8.61), but the risks of VTE, AMI, ischemic and non-ischemic stroke and PCI were increased also 2- to 3-fold.

Conclusions

We found an increased risk for all-cause mortality and acute cardiovascular events in patients with hyperthyroidism.