The results of observational studies of causal effects are potentially biased due to confounding. Various methods have been proposed to control for confounding in observational studies. Eight basic aspects of confounding adjustment are described, with a focus on correction for confounding through covariate adjustment using regression analysis. These aspects should be considered when planning an observational study of causal effects or when assessing the validity of the results of such a study.
Rolf H H Groenwold and Olaf M Dekkers
Maria Fleseriu, Olaf M Dekkers and Niki Karavitaki
Patients with pituitary tumours, ensuing hormonal abnormalities and mass effects are usually followed in multidisciplinary pituitary clinics and can represent a management challenge even during the times of non-pandemic. The COVID-19 pandemic has put on hold routine medical care for hundreds of millions of patients around the globe, while many pituitary patients’ evaluations cannot be delayed for too long. Furthermore, the majority of patients with pituitary tumours have co-morbidities potentially impacting the course and management of COVID-19 (e.g. hypopituitarism, diabetes mellitus, hypertension, obesity and cardiovascular disease). Here, we summarize some of the diagnostic and management dilemmas encountered, and provide guidance on safe and as effective as possible delivery of care in the COVID-19 era. We also attempt to address how pituitary services should be remodelled in the event of similar crises, while maintaining or even improving patient outcomes. Regular review of these recommendations and further adjustments are needed, depending on the evolution of the COVID-19 pandemic status. We consider that the utilization of successful models of pituitary multidisciplinary care implemented during the COVID-19 pandemic should continue after the crisis is over by using the valuable and exceptional experience gained during these challenging times.
Rolf H H Groenwold and Olaf M Dekkers
The validity of any biomedical study is potentially affected by measurement error or misclassification. It can affect different variables included in a statistical analysis, such as the exposure, the outcome, and confounders, and can result in an overestimation as well as in an underestimation of the relation under investigation. We discuss various aspects of measurement error and argue that often an in-depth discussion is needed to appropriately assess the quality and validity of a study.
Saskia le Cessie, Jelle J Goeman and Olaf M Dekkers
Wiebke Arlt, Olaf M Dekkers, Juliane Léger and Robert K Semple
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.
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.
Olaf M Dekkers, Erzsébet Horváth-Puhó, Suzanne C Cannegieter, Jan P Vandenbroucke, Henrik Toft Sørensen and Jens Otto L Jørgensen
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.
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.
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.
We found an increased risk for all-cause mortality and acute cardiovascular events in patients with hyperthyroidism.
Mette Søgaard, Dóra Körmendiné Farkas, Vera Ehrenstein, Jens Otto Lunde Jørgensen, Olaf M Dekkers and Henrik Toft Sørensen
The association between thyroid disease and breast cancer risk remains unclear. We, therefore examined the association between hypothyroidism, hyperthyroidism and breast cancer risk.
This was a population-based cohort study.
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.
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.
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.
Renate T de Jongh, Paul Lips, Kelly J Rijs, Natasja M van Schoor, Mark H H Kramer, Jan P Vandenbroucke and Olaf M Dekkers
Vitamin D receptor (VDR) polymorphisms are associated with a variety of diseases, which may translate into an effect on mortality.
To investigate the associations between VDR gene variants and mortality among older people.
The analyses were conducted in a population-based, prospective cohort of the Longitudinal Aging Study Amsterdam. Adequate DNA analysis was performed in 923 men and women (≥65 years). We aimed to assess the associations between mortality and the VDR polymorphism FokI, three haplotypes of the Cdx2 and GATA polymorphisms, and three haplotypes of the BsmI, ApaI, and TaqI polymorphisms.
During the median follow-up of 10.7 years, 480 participants deceased (51%). Homozygosity for the Cdx2 – GATA haplotype 1 allele was associated with a 30% higher mortality risk compared to the absence of alleles (hazard ratios (HR) 1.30, 95% confidence intervals (CI) 1.01–1.68). Adjustment for cardiovascular risk factors and 25-hydroxyvitamin D levels did not affect this HR. The number of copies of the Cdx2 – GATA haplotype 1 allele was associated, although not significantly, with an increased risk of osteoporotic fractures (0 copies=reference, HR, 95% CI: 1 copy 2.01, 0.99–4.07 and 2 copies 1.81, 0.87–4.18). After adjustment for osteoporotic fractures, homozygosity for the Cdx2 – GATA haplotype 1 allele was no longer associated with higher mortality risk (HR 1.08, 95% CI 0.83–1.41).
The Cdx2 – GATA haplotype 1 allele was related to increased mortality risk, which may be partly explained by osteoporotic fractures. As the biological mechanism is uncertain and this study size is limited, our results should be interpreted as hypothesis generating.