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Margit Kriegbaum,1 Bent Struer Lind,2 Mia Klinten Grand,1 Christen Lykkegaard Andersen1,3 1The Copenhagen Primary Care Laboratory (CopLab) Database, Research Unit for General Practice and Section of General Practice, Department of Public Health, University of Copenhagen, Copenhagen, Denmark; 2Department of Clinical Biochemistry, Copenhagen University Hospital Hvidovre, Copenhagen, Denmark; 3Department of Haematology, University Hospital Copenhagen, Rigshospitalet, Copenhagen, DenmarkCorrespondence: Margit Kriegbaum, Research Unit for General Practice and Section of General Practice, Department of Public Health, University of Copenhagen, Øster Farimagsgade 5, 1353 København K, Denmark, Tel +45 35337326, Fax +45 35327629, Email makr@sund.ku.dkBackground: The Copenhagen General Practice Laboratory (CGPL) was founded in 1922 to provide paraclinical analyses to the primary health-care sector in Copenhagen. At the end of 2015, CGPL was closed and the CopLab database was established to make CGPL data available for research.Methods: We isolated tests performed at the CGPL with clinically relevant test results. The database was linked to national registers containing health, social, and demographic information. Results are presented with descriptive statistics showing counts, percentages, medians, and interquartile ranges (IQR).Results: The CopLab database includes 1,373,643 unique individuals from primary care with test results from laboratory analyses of blood/urine/semen as well as cardiac and lung function tests collected by CGPL from greater Copenhagen from 2000 to 2015. The CopLab database holds nearly all test results requested by general practitioners throughout years 2000 to 2015 for residents in the greater Copenhagen area. The median age of the individuals was 51 years and 59.7% were females. Each individual has a median of 4 requisitions. More than 1 million participants are currently alive and living in Denmark and may be followed in national registries such as the Danish National Patient Registry, Laboratory Database, National Prescription Database etc.Keywords: laboratory database, population-based cohort, register studies, clinical biochemistry, epidemiology

Purpose: Growing elderly populations worldwide have sparked interest in factors promoting healthy aging. Diet and other lifestyle patterns are key factors for healthy ageing; however, evidence is sparse for specific dietary guidelines that are easily implemented in everyday life. Whole grains constitute specific dietary components with unexplored potential in healthy ageing., Methods: We applied an illness-death multistate model to assess the association between whole-grain intake and life expectancy, both with and without disease, over a 20-year period. Healthy ageing was defined as absence of cancer, ischemic heart disease, stroke, type 2 diabetes, asthma, chronic obstructive pulmonary disease, and dementia during follow-up., Results: Based on information from 22,606 men and 25,468 women in the Danish Diet, Cancer and Health cohort, followed for an average of 13.8 and 17.5 years, respectively, a doubling in whole-grain intake was associated with 0.43 (95% CI: 0.33-0.52) and 0.15 (0.06-0.24) additional years without disease for men and women, respectively. Comparing the highest and lowest quartiles of whole-grain intake, with a special emphasis on men, we found that those with the highest intake lived, on average, one year longer without disease compared to those with the lowest intake. Additionally, although a high intake of whole grains yielded longer life expectancy, the duration of living with disease was shorter., Conclusion: Intake of whole grains in mid-life was associated with healthy ageing looking 20 years ahead., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Context: Thyroid hormones are critical for neural development, and during the first trimester of pregnancy the fetus relies fully on maternal thyroid hormone production., Objective: To investigate the associations between maternal thyroid hormone levels in the first trimester with the child's school performance, risk of attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD)., Methods: From the Copenhagen Primary Care Laboratory Pregnancy Database information on first trimester TSH and fT4 measurements in mothers of children born in 2000-2014 were linked with information on the child's standardized test scores in school, ADHD (patient record diagnoses and medication) and ASD (patient record diagnoses) until end of 2018. Associations of TSH and fT4 with the outcomes were individually assessed by linear mixed models and Cox regression models. The analyses were stratified by preexisting maternal thyroid disorders., Results: TSH measurements were available for 17,909 mother-child dyads. Among those with children born in 2000-2009, 6,126 had a standardized school test score and were analyzed for the association between maternal thyroid hormone levels and child's school performance, and no support for an association was found. The association between thyroid hormone levels and child's risk of ADHD and ASD were analyzed for the 17,909 dyads and with no support for an association between thyroid hormone levels and these neurodevelopmental disorders. Stratification by preexisting maternal thyroid disorders did not affect the results., Conclusions: We found no evidence for associations between first trimester maternal thyroid hormone levels and child's school performance, or risk of ADHD or ASD., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Severe mental illness (SMI) is associated with increased cardiovascular risk. Dyslipidaemia is a potentially modifiable risk factor, which may be inadequately managed in patients with SMI., Objectives: To assess management of dyslipidaemia in patients with SMI versus healthy controls (HCs) in 2005 and 2015., Design and Methods: Using Danish registers, we identified adult patients with SMI in the Greater Copenhagen Area (schizophrenia spectrum disorders or bipolar disorder) with ⩾1 general practitioner contact in the year before 2005 and 2015, respectively, and HCs without SMI matched on age and gender (1:5). Outcomes were lipid-profile measurements, presence of dyslipidaemia and redemption of lipid-lowering pharmacotherapy. Differences in outcomes between patients with SMI and controls were measured with multivariable logistic regression., Results: We identified 7217 patients with SMI in 2005 and 9939 in 2015. After 10 years, patients went from having lower odds of lipid measurements to having higher odds of lipid measurements compared with HCs [odds ratio (OR) 2005 0.70 (99% confidence interval (CI) 0.63-0.78) versus OR 2015 1.34 (99% CI 1.24-1.44); p 2005 versus 2015  < 0.01]. Patients had higher odds of dyslipidaemia during both years [OR 2005 1.43 (99% CI 1.10-1.85) and OR 2015 1.23 (99% CI 1.08-1.41)]. Patients went from having lower odds of receiving lipid-lowering pharmacotherapy to having higher odds of receiving lipid-lowering pharmacotherapy [OR 2005 0.77 (99% CI 0.66-0.89) versus OR 2015 1.37 (99% CI 1.24-1.51); p 2005 versus 2015  < 0.01]. However, among persons at high cardiovascular risk, patients had lower odds of receiving lipid-lowering pharmacotherapy during both years, including subsets with previous acute coronary syndrome [OR 2005 0.30 (99% CI 0.15-0.59) and OR 2015 0.44 (99% CI 0.24-0.83)] and ischaemic stroke or transient ischaemic attack (TIA) [OR 2005 0.43 (99% CI 0.26-0.69) and OR 2015 0.61 (99% CI 0.41-0.89)]., Conclusion: These results imply an increased general awareness of managing dyslipidaemia among patients with SMI in the primary prophylaxis of cardiovascular disease. However, secondary prevention with lipid-lowering drugs in patients with SMI at high cardiovascular risk may be lacking., Competing Interests: BE is part of the Advisory Board of Eli Lilly Denmark A/S, Janssen-Cilag, Lundbeck Pharma A/S, and Takeda Pharmaceutical Company Ltd, and has received lecture fees from Bristol-Myers Squibb, Boehringer Ingelheim, Otsuka Pharma Scandinavia AB, Eli Lilly Company and Lundbeck Pharma A/S. FKK has served on scientific advisory panels and/or been part of speaker’s bureaus for, served as a consultant to and/or received research support from Amgen, AstraZeneca, Boehringer Ingelheim, Carmot Therapeutics, Eli Lilly, Gubra, MedImmune, MSD/Merck, Mundipharma, Norgine, Novo Nordisk, Sanofi, ShouTi, Zealand Pharma and Zucara. The other authors declare no conflict of interests., (© The Author(s), 2023.)

Objective: Diabetes is a risk factor for atrial fibrillation (AF), and increases the risk of thromboembolic events in persons with AF. However, the link between the two conditions is not fully elucidated. Few studies have investigated the association of dysglycemia and incident AF. We investigated the risk of incident AF and prognosis according to diabetes status., Research Design and Methods: The Copenhagen Primary Care Laboratory Database was merged with data on medical prescriptions, in- and outpatient contacts and vital status. The risk of AF according to diabetes status was investigated by use of Cox regression models., Results: Of 354.807 individuals with a hemoglobin A1c (HbA 1c ) measurement, 28.541 (8 %) had known diabetes, 13.038 (4 %) had new onset diabetes and 27.754 (8 %) had prediabetes (HbA 1c 42-47 mmol/mol). Persons with dysglycemia (HbA 1c  > 42 mmol/mol) and diabetes were older, more were men, they had lower level of education and were more likely to be living alone. We observed a gradual increase in risk of developing AF from HbA 1c levels of 40 to 60 mmol/mol. In adjusted analyses we found a stepwise increase in hazard of AF from normoglycemia over prediabetes to persons with diabetes (no diabetes: 1.00 [ref.]; prediabetes: 1.12 [1.08-1.16]; new-onset diabetes: 1.16 [1.10-1.22]; known diabetes: 1.15 [1.11-1.20]). Persons with known diabetes had a significant higher hazard of stroke, cardiovascular and all-cause mortality., Conclusion: Increasing levels of HbA 1c were associated with an increased hazard of developing AF. Persons with new onset of diabetes and those with known diabetes had similar hazard of developing AF, however persons with known diabetes had a significant higher hazard of stroke, cardiovascular- and all-cause mortality., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: The prevalence of chronic kidney disease (CKD) is increasing globally. Early diagnosis in primary care may have a role in ensuring proper intervention. We aimed to determine the prevalence and outcome of CKD in primary care., Methods: We performed an observational cohort study in primary care in Copenhagen (2001-2015). Outcomes were stroke, myocardial infarction (MI), heart failure (HF), peripheral artery disease (PAD), all-cause- and cardiovascular mortality. We combined individuals with normal kidney function and CKD stage 2 as reference. We conducted cause-specific Cox proportional regressions to calculate the hazard ratios for outcomes according to CKD group. We explored the associations between kidney function and the outcomes examined using eGFR as a continuous variable modelled with penalised splines. All models were adjusted for age, gender, diabetes, hypertension, existing CVD, heart failure, LDL cholesterol and use of antihypertensive treatment., Results: We included 171,133 individuals with at least two eGFR measurements of which the majority (n = 157,002) had eGFR > 60 ml/min/1.73m 2 at index date, and 0.05% were in CKD stage 5. Event rates were low in eGFR > 60 ml/min/1.73m 2 but increased in those with higher stages of CKD. In adjusted analyses we observed an increase in hazard rates for every outcome with every increment in CKD stage. Compared to the reference group, individuals in CKD stage 4 had double the hazard rate of PAD, MI, cardiovascular and all-cause mortality., Conclusions: Our data from a large primary care cohort demonstrate an early increase in the risk of adverse outcomes already at CKD stage 3. This underlines the importance of studying early intervention in primary care., (© 2023. The Author(s).)

Background: Insulin resistance is a critical cause of metabolic dysfunctions. Metabolic dysfunction is common in patients with cancer and is associated with higher cancer recurrence rates and reduced overall survival. Yet, insulin resistance is rarely considered in the clinic and thus it is uncertain how frequently this condition occurs in patients with cancer., Methods: To address this knowledge gap, we performed a systematic review and a meta-analysis guided by the Preferred Items for Systematic Review and Meta-Analyses (PRISMA) statement. We included studies assessing insulin resistance in patients with various cancer diagnoses, using the gold-standard hyperinsulinemic-euglycemic clamp method. Studies eligible for inclusion were as follows: (1) included cancer patients older than 18 years of age; (2) included an age-matched control group consisting of individuals without cancer or other types of neoplasms; (3) measured insulin sensitivity using the hyperinsulinemic-euglycemic clamp method. We searched the databases MEDLINE, Embase, and Cochrane Central Register of Controlled Trials for articles published from database inception through March 2023 with no language restriction, supplemented by backward and forward citation searching. Bias was assessed using funnel plot., Findings: Fifteen studies satisfied the criteria. The mean insulin-stimulated rate of glucose disposal (Rd) was 7.5 mg/kg/min in control subjects ( n  = 154), and 4.7 mg/kg/min in patients with a cancer diagnosis ( n  = 187). Thus, the Rd mean difference was -2.61 mg/kg/min [95% confidence interval, -3.04; -2.19], p <.01). Heterogeneity among the included studies was insignificant ( p =.24)., Interpretation: These findings suggest that patients with a cancer diagnosis are markedly insulin resistant. As metabolic dysfunction in patients with cancer associates with increased recurrence and reduced overall survival, future studies should address if ameliorating insulin resistance in this population can improve these outcomes thereby improving patient care.Key pointsMetabolic dysfunction increases cancer recurrence rates and reduces survival for patients with cancer.Insulin resistance is a critical cause of metabolic dysfunctions.To date, no comprehensive compilation of research investigating insulin resistance in cancer patients has been produced.In this meta-analysis, we found that patients with various cancers were markedly insulin-resistant.

Aims: Primary care plays an integral role in the management of type 2 diabetes (T2D). We investigated in a large group of individuals in this setting the biochemical profiles, pharmacological management and clinical outcomes as well as their changes over time., Methods: This is a register-based study including relevant laboratory test results requested between 2000 and 2015 by general practitioners in the greater Copenhagen area. We identified 72,044 individuals with T2D on whom data concerning prescription medicine and clinical outcomes were obtained from national registries., Results: The number of individuals with T2D greatly increased from 2001 to 2015. Hemoglobin A 1c , estimated glomerular filtration rate and urine albumin creatinine ratio did not change, but cholestrol levels improved. The proportion redeeming anti-diabetics remained around 80%, with an increase for metformin. The use of cardiovascular drugs increased. All-cause and especially cardiovascular mortality decreased over the period. Hospital admissions for non-fatal cardiovascular events dropped., Conclusion: The number of individuals with T2D in primary care increased dramatically whereas pharmacological management, control of risk factors and clinical outcomes seem to have improved. Nevertheless, a conspicuous minority did not receive diabetes-related medication., Competing Interests: Conflicts of interest NSH reports stock ownership in Novo Nordisk A/S and Akcea Therapeutics Inc. FP reports having received research grants from AstraZeneca, Novo Nordisk and Novartis and lecture fees from Novartis, Eli Lilly, MSD, AstraZeneca, Sanofi, Novo Nordisk and Boehringer Ingelheim and having served as a consultant for Astra Zeneca, Bayer, Amgen, Novo Nordisk and MSD. MC reports having received lecture fees from Novo Nordisk and Boehringer Ingelheim. The other authors report no conflicts of interest., (Copyright © 2022 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.)

Background: Elastography can be measured with different imaging techniques and is increasingly used for noninvasive assessment of hepatic fibrosis. Little is known about the performance, and interrelation of different elastographic techniques, in prediction of hepatic fibrosis in pediatric liver disease. Objectives: We aimed to determine the discriminatory value for advanced fibrosis (Metavir F3-4) and evaluate the applicability of 2D shear wave ultrasound elastography (USe), Transient Elastography (TE) and Magnetic Resonance elastography (MRe) in pediatric liver disease. Methods: In patients with pediatric liver disease aged 0−19 years, USe, TE and MRe were compared with histopathological fibrosis stage. Multivariate logistic regression models for advanced fibrosis were considered. Discriminative performance was assessed by the area under the receiver operating characteristic curve and the Brier Score. Primary analyses included complete cases. Multiple imputation was used as sensitivity analysis. Results: In 93 histologically evaluated patients USe, TE and MRe were performed 89, 93 and 61 times respectively. With increased liver stiffness values, significantly increased odds for presenting F3-4 were seen in individual models for ALT < 470 U/L, whereas the effect for ALT > 470 U/L was non-significant. Area under the curve and Brier Score for discrimination of advanced fibrosis were 0.798 (0.661−0.935) and 0.115 (0.064−0.166); 0.862 (0.758−0.966) and 0.118 (0.065−0.171); 0.896 (0.798−0.994) and 0.098 (0.049−0.148) for USe, TE and MRe respectively. No significant increase in discriminatory ability was found when combining elastographic modalities. Conclusions: In pediatric liver disease, USe, TE and MRe had a good discriminatory ability for assessment of advanced liver fibrosis, although TE and MRe performed best. In most children with pediatric liver disease, TE is a reliable and easily applicable measure., Competing Interests: The authors declare no conflict of interest.

The association between ferritin and transferrin saturation (TS), respectively, and all-cause mortality is unclear. Furthermore, the influence of concurrent inflammation has not been sufficiently elucidated. We investigated these associations and the effect of concurrently elevated C-reactive protein (CRP), and accordingly report the levels associated with lowest all-cause mortality for females and males with and without inflammation.Blood test results from 161,921 individuals were included. Statistical analyses were performed in sex-stratified subpopulations, with ferritin or TS level as continuous exposure variables, and were adjusted for age, co-morbidity and inflammation status using CRP. An interaction was used to investigate whether the effect of ferritin or TS on all-cause mortality was modified by inflammation status (CRP ≥ 10 mg/L or CRP < 10 mg/L). Low and high ferritin and TS levels were respectively associated with increased all-cause mortality in females and in males. These associations persisted with concurrent CRP ≥ 10 mg/L. The ferritin level associated with lowest mortality was 60 µg/L for females and 125 µg/L for males with CRP < 10 mg/L. It was 52 µg/L for females and 118 µg/L for males with CRP ≥ 10 mg/L. The TS level associated with lowest mortality was 33.9% for females and 32.3% for males with CRP < 10 mg/L. It was 28.7% for females and 30.6% for males with CRP ≥ 10 mg/L.Our findings can nuance clinical interpretation and further aid in defining recommended ranges for ferritin and TS.

Background: The dynamics of pre-diagnostic lymphocytosis in patients with ensuing chronic lymphocytic leukemia (CLL) need to be explored as a better understanding of disease progression may improve treatment options and even lead to disease avoidance approaches. Our aim was to investigate the development of lymphocytosis prior to diagnosis in a population-based cohort of patients with CLL and to assess the prognostic information in these pre-diagnostic measurements., Methods: All patients diagnosed with CLL in the Greater Copenhagen area between 2008 and 2016 were included in the study. Pre-diagnostic blood test results were obtained from the Copenhagen Primary Care Laboratory Database encompassing all blood tests requested by Copenhagen general practitioners. Using pre-diagnostic measurements, we developed a model to assess the prognosis following diagnosis. Our model accounts for known prognostic factors and corresponds to lymphocyte dynamics after diagnosis., Results: We explore trajectories of lymphocytosis, associated with known recurrent mutations. We show that the pre-diagnostic trajectories are an independent predictor of time to treatment. The implementation of pre-diagnostic lymphocytosis slope groups improved the model predictions (compared to CLL-IPI alone) for treatment throughout the period. The model can manage the heterogeneous data that are to be expected from the real-world setting and adds further prognostic information., Conclusions: Our findings further knowledge of the development of CLL and may eventually make prophylactic measures possible., Competing Interests: Competing interestsC.U.N. received grants/consultancy fees from AbbVie, Janssen, Gilead, AstraZeneca, CSL Behring, Takeda, Octapharma, Roche, and Novartis outside of this study. M.A.A., M.K.G., C.B., V.S., and C.L.A. report no conflict of interest., (© The Author(s) 2022.)

To investigate possible biochemical abnormalities associated with celiac disease (CD) antibody positivity in a primary health care setting and thereby identify predictors that could potentially reduce diagnostic delay and underdiagnosis of CD. This observational cohort study included measurements of CD antibodies in the Copenhagen Primary Care Laboratory (CopLab) database from 2000 to 2015; CD antibody positivity was defined as tissue transglutaminase antibody IgA or IgG ≥ 7 kU/L and/or deamidated gliadin peptide antibody IgG ≥ 10 kU/L. Individuals with a prior diagnosis of CD were excluded. We examined differences between individuals with positive and negative CD antibody tests regarding the results of biochemical tests performed six months before and one month after the date of the CD antibody test. We identified 76,265 measurements of CD antibodies during 2000-2015, and 57,061 individuals met the inclusion criteria (706 antibody-positive and 56,355 antibody-negative). We found lower ferritin, hemoglobin, cobalamin and folic acid levels and higher levels of transferrin, ALAT (alanine transaminase), and alkaline phosphate among individuals with a positive CD antibody test. Furthermore, we illustrated more measurements below the sex-specific reference intervals for hemoglobin, mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), ferritin, cobalamin and folic acid among individuals with a positive CD antibody test. This study identified several biochemical abnormalities associated with CD antibody positivity among individuals referred to CD antibody testing. The pattern of abnormalities suggested that micronutrient deficiencies were prevalent among CD antibody-positive individuals, confirming malabsorption as a sign of CD. These findings illustrate the possibility of reducing diagnostic delay and underdiagnosis of CD., (© 2022. The Author(s).)

Technological advances have made it possible to offer home-based chemotherapy to patients without health care professionals being present. Prior studies on effects of home-based treatment lack inclusion of patients with hematologic malignancies. We present data from a multicenter single-arm feasibility and safety study of home-based intensive chemotherapy in patients with newly diagnosed acute myeloid leukemia and their quality of life and psychological wellbeing. This national study included patients from six sites in Denmark who received intensive chemotherapy on programmed CADD Solis infusion pumps through a central venous catheter and were also managed as outpatients during treatment-induced pancytopenia. Data are presented from 104 patients, receiving 272 treatments with 1.096 (mean 4.57, SD 3.0) home infusion days out of 1.644 treatment days (67 %). Sixty-two of 168 (36.9 %) reinduction and consolidation treatment cycles ensuing pancytopenia phases were solely handled in the outpatient clinic. Patients reported high satisfaction with home-based treatment, which had a positive influence on their ability to be involved in their treatment and be socially and physically active. No unexpected events occurred during the intervention. Overall, patients improved in all quality of life outcomes over time. Home-based intensive chemotherapy treatment was feasible and safe in this population. ClinicalTrials.gov identifier: NCT04904211., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Lipid levels in blood have decreased considerably during the past decades in the general population partly due to use of statins. This study aims to investigate the trends in lipid levels between 2001 and 2018 in a statin-free population from primary health care, overall and by sex and age., Methods: In a cohort of 634,119 patients from general practice with no diagnoses or medical treatments that affected lipid levels of total cholesterol (TC; n = 1,574,339) between 2001 and 2018 were identified. Similarly, measurements of low-density lipoprotein cholesterol (LDL-C; n = 1,302,440), high-density lipoprotein cholesterol (HDL-C; n = 1,417,857) and triglycerides (TG; n = 1,329,477) were identified., Results: Mean TC decreased from 5.64 mmol/L (95% CI: 5.63-5.65) in 2001 to 5.17 mmol/L (95% CI: 5.16-5.17) in 2018 while LDL-C decreased from 3.67 mmol/L (95% CI: 3.66-3.68) to 3.04 mmol/L (95% CI: 3.03-3.04). Women aged 70-74 years experienced the largest decreases in TC levels corresponding to a decrease of 0.7 mmol/L. The decrease in LDL-C levels was most pronounced in men ≥85 years with a decrease of 0.9 mmol/L. For both genders, TC and LDL-C levels increased with advancing age until around age 50. After menopause the women had higher TC and LDL-C levels than the men. The median (geometric mean) TG level decreased by 0.4 mmol/L from 2001 to 2008, after which it increased slightly by 0.1 mmol/L until 2018. During life the TG levels of the men were markedly higher than the women's until around age 65-70. HDL-C levels showed no trend during the study period., Conclusions: The levels of TC and LDL-C decreased considerably in a statin-free population from primary health care from 2001 to 2018. These decreases were most pronounced in the elderly population and this trend is not decelerating. For TG, levels have started to increase, after an initial decrease., (© 2021. The Author(s).)

Objective: A decrease over time in thyroid stimulating hormone (TSH) levels when initiating levothyroxine (L-T4) therapy for hypothyroidism has been reported, where treatment most often is initiated with TSH levels below 10 mIU/L. The primary objective of this study was to investigate whether this lower TSH threshold resulted in an increased number of overtreated patients., Design and Method: Retrospective cohort study comprising inhabitants in Copenhagen had TSH measurements requested by general practitioners which led to a new prescription of L-T4 between 2001 and 2012. Over- and under- treatment were defined as TSH <0.1 mIU/L or above 10 mIU/mL, respectively, in three consecutive measurements. Data were analyzed by Aalen-Johansen estimators and Cox proportional hazards models., Results: In total, 14 533 initiations of L-T4 were included in the study. The cumulative risk of being over- or undertreated was 4.7 and 7.4% after 10 years. The hazard of overtreatment was higher among women, younger adults, and with lower initial TSH levels. The hazard of overtreatment decreased over the time period from 2001 to 2012. Among overtreated individuals, the chance of returning to a normal TSH was about 55% after 10 years. In 18% of the cases, L-T4 therapy was initiated on TSH levels less than 5 mIU/L., Conclusion: Although a still decreasing threshold for initiating L-T4 therapy is known, the risk of overtreatment (and undertreatment) was low and lessened in the period 2001-2012 among Danish primary care patients. Nevertheless, as many as 18% were started on L-T4 with normal TSH levels.

Objective: The incidence of hypothyroidism is not expected to differ by socioeconomic factors. However, the decision to test and initiate treatment may differ. We aimed to examine whether educational level influences the probability of thyroid stimulation hormone (TSH)-measurement and initiation of levothyroxine treatment., Design: Citizens in the greater Copenhagen Area during 2001-2015 were included. Individual-level data on educational level, diagnoses, GP-contact, TSH-measurement and medication were derived from administrative and healthcare registers. The relative risks (RR) between educational levels of annual TSH-measurement and treatment initiation following a TSH-measurement were analysed in Poisson regression models with generalized estimation equations., Results: A TSH-measurement was performed in 19% of 9,390,052 person years. The probability of TSH-measurement was higher with short (RR 1.16 [95% CI 1.15-1.16]) and medium (RR 1.11 [95% CI 1.06-1.12]) compared with long education. Treatment was initiated after 0.8% of 2,049,888 TSH-measurements. For TSH < 5 mIU/L, RR for treatment initiation ranged between 0.47 (95%CI 0.39-0.57) and 0.78 (95%CI 0.67-0.91) for short and medium compared with long education. For TSH 5-10 mIU/L, there was no statistically significant difference. For TSH > 10 mIU/L, RR was 1.07 (95% CI 1.02-1.12) for short and 1.08 (95% CI 1.03-1.13) for medium compared with long education., Conclusion: The probability of TSH-measurement was higher with shorter education, and the probability of treatment initiation with TSH > 10 mIU/L was marginally higher with short-medium education compared with long education. However, the probability of treatment initiation with TSH < 5 mIU/L, that is treatment incongruous with guidelines, was substantially higher in persons with long education., (© 2021 John Wiley & Sons Ltd.)

Purpose: The Copenhagen Primary Care Laboratory Pregnancy (CopPreg) database was established based on data from The Danish Medical Birth Register and the Copenhagen Primary Care Laboratory (CopLab) database. The aim was to provide a biomedical and epidemiological data resource for research in early disease programming (eg, parental clinical biomarker levels and pregnancy/ birth outcomes or long-term health in the offspring)., Participants: The cohort consisted in total of 203 608 women (with 340 891 pregnancies) who gave birth to 348 248 children and with 200 590 related fathers. In this paper, we focused on women and fathers who had clinical test requisitions prior to and during pregnancy, and on all children. Thus, the cohort in focus consisted of 203 054 pregnancies with requisitions on 147 045 pregnant women, 39 815 fathers with requisitions during periconception and 65 315 children with requisitions., Findings to Date: In addition to information on pregnancy and birth health status and general socio-demographic data, over 2.2 million clinically relevant test results were available for pregnancies with requisitions, over 1.5 million for children and over 600 000 test results were available for the fathers with requisitions during periconception. These were ordered by general practitioners in the primary care setting only and included general blood tests, nutritional biomarkers (macronutrients and micronutrients) and hormone tests. Information on tests related to infections, allergies, heart and lung function and sperm analyses (fathers) were also available., Future Plans: The CopPreg database provides ready to use and valid data from already collected, objectively measured and analysed clinical tests. With several research projects planned, we further invite national and international researchers to use this vast data resource. In a coming paper, we will explore and discuss the indication bias in our cohort., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Increased public attention toward health and quality-of-life issues has led to more intensified screening for various medical conditions, including hypothyroidism. A falling serum thyrotropin (s-TSH) at initiation of levothyroxine (LT4) treatment has been reported in the United Kingdom between 2001 and 2009, indicating a falling TSH threshold, which may lead to less benefit from therapy and possibly overtreatment. The aim of this study was to investigate changes in s-TSH threshold used by general practitioners to initiate LT4 therapy between 2001 and 2015 in Copenhagen. Methods: Retrospective analysis was conducted of all s-TSH measurements between 2001 and 2015 performed at the general practitioners' joint laboratory merged with The Danish Register of Medicinal Products Statistics and The Danish National Patient Registry. For each year, both the median s-TSH at therapy initiation and the estimated treatment threshold were calculated from all s-TSH measurements performed in that year, representing the s-TSH level where the estimated probability of starting LT4 therapy was 50%. Results: A total of 929,684 individuals with 2,975,277 s-TSH measurements were included in the calculations. The size and composition of the study population remained virtually unchanged. During the study period, the number of performed s-TSH measurements increased from 110,886 to 292,911 (164%), and the number of patients initiating LT4 therapy increased from 786 to 1825 (132%), though this was comparably unchanged from 2010 to 2015. The median s-TSH at therapy initiation decreased from 10 mIU/L (interquartile range 5.2-29.7 mIU/L) in 2001 to 6.8 mIU/L (interquartile range 5.1-11 mIU/L) in 2015, while the estimated treatment threshold decreased from 28.3 mIU/L [confidence interval 21.0-40.2 mIU/L] in 2001 to 14.2 mIU/L [confidence interval 12.0-18.0 mIU/L] in 2007. In 2015, 25% of patients started LT4 therapy with s-TSH ≤5 mIU/L, and during the entire period, 50% of patients started therapy with a single s-TSH measurement >5 mIU/L. Conclusions: This study performed on a sizeable primary care population demonstrates a considerable fall in the threshold for initiating LT4 therapy in hypothyroid patients. This increases the risk of futile treatment as well as overtreatment.

Uveitis is characterised as a recurrent inflammation of the eye and an ongoing inflammation can have severe impact on the visual acuity of the patient. The Rotterdam Eye Hospital has been collecting data on every uveitis patient visiting the hospital since 2000. We propose a joint model for the inflammation and visual acuity with the purpose of making dynamic predictions. Dynamic prediction models allow predictions to be updated during the follow-up of the patient based on the patient's disease history. The joint model consists of a submodel for the inflammation, the event history outcome, and one for the visual acuity, the longitudinal outcome. The inflammation process is described with a two-state reversible multistate model, where transition times are interval censored. Correlated log-normal frailties are included in the multistate model to account for the within eye and within patient correlation. A linear mixed model is used for the visual acuity. The joint model is fitted in a two-stage procedure and we illustrate how the model can be used to make dynamic predictions. The performance of the method was investigated in a simulation study. The novelty of the proposed model includes the extension to a multistate outcome, whereas, previously, the standard has been to consider survival or competing risk outcomes. Furthermore, it is usually the case that the longitudinal outcome affects the event history outcome, but in this model, the relation is reversed., (© 2018 John Wiley & Sons, Ltd.)

Aims: The urinary marker of RNA oxidation, 8‑oxo‑7,8‑dihydroguanosine (8-oxoGuo), but not the corresponding marker of DNA oxidation, 8‑oxo‑7,8‑dihydro‑2'‑deoxyguanosine (8-oxodG), is a prognostic biomarker in patients with type 2 diabetes (T2D). The aim of the present study was to investigate the effect of structured personal care (individualized multifactorial treatment) versus standard care on RNA oxidation level in patients with T2D and to assess if the effect of structured personal care on all-cause and diabetes-related mortality was modified by RNA oxidation level., Methods: Urine samples were analyzed for 8-oxoGuo/8-oxodG from 1381 newly diagnosed T2D patients from the cluster randomized trial Diabetes Care in General Practice cohort, and 970 patients were reexamined after six years of intervention., Results: The yearly variation in RNA oxidation levels were not significantly different between the structured personal care group and standard care group. The effect of treatment on all-cause and diabetes-related mortality was not modified by the level of RNA oxidation. No changes in DNA oxidation were seen., Conclusions: Structured personal care does not influence RNA oxidation level nor is it better for patients with high RNA oxidation level. Thus, structured personal care may not impact the disease-related aspects identified by RNA oxidation level in T2D patients., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Pseudo-observations have been introduced as a way to perform regression analysis of a mean value parameter related to a right-censored time-to-event outcome, such as the survival probability or the restricted mean survival time. Since the introduction of the approach there have been several extensions from the original setting. However, the proper definition and performance of pseudo-observations under left-truncation has not yet been addressed. Here, we look at two types of pseudo-observations under right-censoring and left-truncation. We explored their performance in a simulation study and applied them to data on diabetes patients with left-truncation., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Measurement of B-type natriuretic peptide (BNP) in plasma may have its greatest potential in primary care, as general practitioners need to rapidly identify patients who warrant further medical review. The aim of the present study was to examine the prognostic information of BNP measurement on all-cause mortality in a large Danish primary care cohort., Methods: This study covered a cohort of Danish primary care patients (n = 61665) with a median follow-up period of 4.36 years (interquartile range, 2.29-6.62 years). BNP was measured in plasma using the ADVIA Centaur/CentaurXP platform. The association of BNP with mortality was assessed with a hazard ratio for all-cause mortality from a multivariable Cox proportional hazards model., Results: Kaplan-Meier curves showed decreasing survival probability with increasing BNP ( P < 0.001). Each doubling of BNP increased mortality by 32.3% (95% CI, 30.8-33.8) when adjusted for sex and age, and by 25.3% (95% CI, 23.8-26.8) when further adjusted for Charlson comorbidity index, hemoglobin, estimated glomerular filtration rate, glycohemoglobin, and thyroid-stimulating hormone. Also, in a subcohort (n = 10824) without biochemical signs of severe kidney failure, anemia, polycythemia, hypothyroidism or hyperthyroidism, or dysregulated diabetes, each doubling of BNP increased mortality by 28.6% (95% CI, 22.8-34.7)., Conclusions: Our results show that even in a primary care population, BNP measurements contain prognostic information regarding all-cause mortality., (© 2018 American Association for Clinical Chemistry.)

In recent years there have been a series of advances in the field of dynamic prediction. Among those is the development of methods for dynamic prediction of the cumulative incidence function in a competing risk setting. These models enable the predictions to be updated as time progresses and more information becomes available, for example when a patient comes back for a follow-up visit after completing a year of treatment, the risk of death, and adverse events may have changed since treatment initiation. One approach to model the cumulative incidence function in competing risks is by direct binomial regression, where right censoring of the event times is handled by inverse probability of censoring weights. We extend the approach by combining it with landmarking to enable dynamic prediction of the cumulative incidence function. The proposed models are very flexible, as they allow the covariates to have complex time-varying effects, and we illustrate how to investigate possible time-varying structures using Wald tests. The models are fitted using generalized estimating equations. The method is applied to bone marrow transplant data and the performance is investigated in a simulation study., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

In multi-state models, the expected length of stay (ELOS) in a state is not a straightforward object to relate to covariates, and the traditional approach has instead been to construct regression models for the transition intensities and calculate ELOS from these. The disadvantage of this approach is that the effect of covariates on the intensities is not easily translated into the effect on ELOS, and it typically relies on the Markov assumption. We propose to use pseudo-observations to construct regression models for ELOS, thereby allowing a direct interpretation of covariate effects while at the same time avoiding the Markov assumption. For this approach, all we need is a non-parametric consistent estimator for ELOS. For every subject (and for every state of interest), a pseudo-observation is constructed, and they are then used as outcome variables in the regression model. We furthermore show how to construct longitudinal (pseudo-) data when combining the concept of pseudo-observations with landmarking. In doing so, covariates are allowed to be time-varying, and we can investigate potential time-varying effects of the covariates. The models can be fitted using generalized estimating equations, and dependence between observations on the same subject is handled by applying the sandwich estimator. The method is illustrated using data from the US Health and Retirement Study where the impact of socio-economic factors on ELOS in health and disability is explored. Finally, we investigate the performance of our approach under different degrees of left-truncation, non-Markovianity, and right-censoring by means of simulation., (Copyright © 2015 John Wiley & Sons, Ltd.)