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Olaf M Dekkers

P values should not merely be used to categorize results into significant and non-significant. This practice disregards clinical relevance, confounds non-significance with no effect and underestimates the likelihood of false-positive results. Better than to use the P value as a dichotomizing instrument, the P values and the confidence intervals around effect estimates can be used to put research findings in a context, thereby taking clinical relevance but also uncertainty genuinely into account.

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Olaf M Dekkers, Pia Burman, and On behalf of the ESE Clinical Committee

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Herman Verloop, Johannes W A Smit, and Olaf M Dekkers

Objective

Thyroid function abnormalities are common during treatment with tyrosine kinase inhibitors such as sorafenib. Suggested causes are direct effects on thyroid tissue and increased extrathyroidal metabolism of serum thyroxine and 3,5,3-triiodothyronine. We postulated that tyrosine kinase inhibitors may affect the peripheral metabolism of TSH as well. The effect of sorafenib on TSH clearance was studied.

Design

In a study of athyreotic patients on TSH suppression therapy, TSH concentrations were measured after recombinant human TSH (rhTSH) injections before and after 26 weeks of sorafenib therapy.

Methods

Before and after the last week of sorafenib therapy, 20 patients with progressive differentiated thyroid carcinoma received a standard dose regimen of two injections 0.9 mg rhTSH on two consecutive days. TSH concentrations were measured 48 h (TSH48 h) and 96 h (TSH96 h) after the first rhTSH injection. The area under the curve (TSH-AUC), reflecting TSH content between 48 and 96 h following rhTSH administration, was calculated.

Results

TSH48 h levels (120.5 mU/l before vs 146.3 mU/l after; P=0.029), TSH96 h levels (22.0 mU/l before vs 35.5 mU/l after; P=0.001), and TSH-AUC (142.7 vs 186.8 mU/l; P=0.001) were significantly higher after sorafenib treatment. Higher sorafenib doses were associated with increased changes in TSH96 h and TSH-AUC. In two patients, TSH levels after sorafenib therapy exceeded 200 mU/l.

Conclusions

Sorafenib therapy is accompanied by higher rhTSH levels, probably due to a decreased TSH clearance. Further studies are recommended to clarify whether a decreased clearance of TSH is sorafenib specific.

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Olaf M Dekkers and Rolf H H Groenwold

The name of the study should properly reflect the actual conduct and analysis of the study. This short paper provides guidance on how to properly name the study design. The first distinction is between a trial (intervention given to patients to study its effect) and an observational study. For observational studies, it should further be decided whether it is cross-sectional or whether follow-up time is taken into account (cohort or case–control study). The distinction prospective-retrospective has two disadvantages: prospective is often seen as marker of higher quality, which is not necessarily true; there is no unifying definition that makes a proper distinction between retrospective and prospective possible.

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Olaf M Dekkers and Rolf H H Groenwold

Immortal time bias should always be considered in an observational study if exposure status is determined based on a measurement or event that occurs after baseline. This bias can lead to an overestimation of an effect, but also to an underestimation, which is explained. Several approaches are illustrated that can be used to avoid immortal time bias in the analysis phase of the study; a time-dependent analysis to avoid immortal time bias optimizes the use of available information.

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Rolf H H Groenwold and Olaf M Dekkers

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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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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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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.