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Zethelius, Björn
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Publications (10 of 104) Show all publications
Rowley, M., Garmo, H., Van Hemelrijck, M., Wulaningsih, W., Grundmark, B., Zethelius, B., . . . Coolen, A. C. (2017). A latent class model for competing risks. Statistics in Medicine, 36(13), 2100-2119.
Open this publication in new window or tab >>A latent class model for competing risks
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2017 (English)In: Statistics in Medicine, ISSN 0277-6715, E-ISSN 1097-0258, Vol. 36, no 13, 2100-2119 p.Article in journal (Refereed) Published
Abstract [en]

Survival data analysis becomes complex when the proportional hazards assumption is violated at population level or when crude hazard rates are no longer estimators of marginal ones. We develop a Bayesian survival analysis method to deal with these situations, on the basis of assuming that the complexities are induced by latent cohort or disease heterogeneity that is not captured by covariates and that proportional hazards hold at the level of individuals. This leads to a description from which risk-specific marginal hazard rates and survival functions are fully accessible, 'decontaminated' of the effects of informative censoring, and which includes Cox, random effects and latent classmodels as special cases. Simulated data confirm that our approach can map a cohort's substructure and remove heterogeneity-induced informative censoring effects. Application to data from the Uppsala Longitudinal Study of Adult Men cohort leads to plausible alternative explanations for previous counter-intuitive inferences on prostate cancer. The importance of managing cardiovascular disease as a comorbidity in women diagnosed with breast cancer is suggested on application to data from the Swedish Apolipoprotein Mortality Risk Study.

Keyword
survival analysis, heterogeneity, informative censoring, competing risks
National Category
Occupational Health and Environmental Health Probability Theory and Statistics
Identifiers
urn:nbn:se:uu:diva-327367 (URN)10.1002/sim.7246 (DOI)000402797900007 ()28233395 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme
Available from: 2017-08-15 Created: 2017-08-15 Last updated: 2018-01-13Bibliographically approved
Häggström, C., Van Hemelrijck, M., Zethelius, B., Robinson, D., Grundmark, B., Holmberg, L., . . . Stattin, P. (2017). Prospective study of Type 2 diabetes mellitus, anti-diabetic drugs and risk of prostate cancer. International Journal of Cancer, 140(3), 611-617.
Open this publication in new window or tab >>Prospective study of Type 2 diabetes mellitus, anti-diabetic drugs and risk of prostate cancer
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2017 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 140, no 3, 611-617 p.Article in journal (Refereed) Published
Abstract [en]

Type 2 diabetes mellitus (T2DM) has consistently been associated with decreased risk of prostate cancer; however, if this decrease is related to the use of anti-diabetic drugs is unknown. We prospectively studied men in the comparison cohort in the Prostate Cancer data Base Sweden 3.0, with data on T2DM, use of metformin, sulfonylurea and insulin retrieved from national health care registers and demographic databases. Cox proportional hazards regression models were used to compute hazard ratios (HR) and 95% confidence intervals (CI) of prostate cancer, adjusted for confounders. The study consisted of 612,846 men, mean age 72 years (standard deviation; SD=9 years), out of whom 25,882 men were diagnosed with prostate cancer during follow up, mean time of 5 years (SD=3 years). Men with more than 1 year's duration of T2DM had a decreased risk of prostate cancer compared to men without T2DM (HR=0.85, 95% CI=0.82-0.88) but among men with T2DM, those on metformin had no decrease (HR=0.96, 95% CI=0.77-1.19), whereas men on insulin (89%) or sulfonylurea (11%) had a decreased risk (HR=0.73, 95% CI=0.55-0.98), compared to men with T2DM not on anti-diabetic drugs. Men with less than 1 year's duration of T2DM had no decrease in prostate cancer risk (HR=1.11, 95% CI=0.95-1.31). Our results gave no support to the hypothesis that metformin protects against prostate cancer as recently proposed. However, our data gave some support to an inverse association between T2DM severity and prostate cancer risk.

What's new? Although Type 2 diabetes mellitus (T2DM) increases the risk of several cancers, multiple studies point toward a significantly inverse relationship between T2DM and prostate cancer risk in men. Use of the anti-diabetic drug metformin is suspected of underlying the association. In this prospective study in Sweden, however, metformin failed to decrease the risk of prostate cancer. By comparison, risk was decreased in association with the use of insulin or sulfonylurea. These findings add some support to an inverse association between T2DM severity and prostate cancer risk.

Keyword
prostate cancer, Type 2 diabetes mellitus, metformin, cohort study, survival analysis
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-314400 (URN)10.1002/ijc.30480 (DOI)000390702500013 ()
Funder
Swedish Research Council, 825-2012-5047Swedish Cancer Society, 2009/941, 11 0471
Available from: 2017-02-08 Created: 2017-02-02 Last updated: 2017-11-29Bibliographically approved
Eeg-Olofsson, K., Zethelius, B., Gudbjornsdottir, S., Eliasson, B., Svensson, A.-M. & Cederholm, J. (2016). Considerably decreased risk of cardiovascular disease with combined reductions in HbA1c, blood pressure and blood lipids in type 2 diabetes: Report from the Swedish National Diabetes Register. Diabetes & Vascular Disease Research, 13(4), 268-277.
Open this publication in new window or tab >>Considerably decreased risk of cardiovascular disease with combined reductions in HbA1c, blood pressure and blood lipids in type 2 diabetes: Report from the Swedish National Diabetes Register
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2016 (English)In: Diabetes & Vascular Disease Research, ISSN 1479-1641, E-ISSN 1752-8984, Vol. 13, no 4, 268-277 p.Article in journal (Refereed) Published
Abstract [en]

Objectives: Assess the effect of risk factors changes on risk for cardiovascular disease and mortality in patients with type 2 diabetes selected from the Swedish National Diabetes Register. Methods: Observational study of 13,477 females and males aged 30-75years, with baseline HbA1c 41-67mmol/mol, systolic blood pressure 122-154mmHg and ratio non-HDL:HDL 1.7-4.1, followed for mean 6.5years until 2012. Four groups were created: a reference group (n=6757) with increasing final versus baseline HbA1c, systolic blood pressure and non-HDL:HDL cholesterol during the study period, and three groups with decreasing HbA1c (n=1925), HbA1c and systolic blood pressure (n=2050) or HbA1c and systolic blood pressure and non-HDL:HDL (n=2745). Results: Relative risk reduction for fatal/nonfatal cardiovascular disease was 35% with decrease in HbA1c only (mean 6 to final 49mmol/mol), 56% with decrease in HbA1c and systolic blood pressure (mean 12 to final 128mmHg) and 75% with combined decreases in HbA1c, systolic blood pressure and non-HDL:HDL (mean 0.8 to final 2.1), all p<0.001 adjusting for clinical characteristics, other risk factors, treatments and previous cardiovascular disease. Similar risk reductions were found for fatal/nonfatal coronary heart disease, fatal cardiovascular disease, all-cause mortality and also in a subgroup of 3038 patients with albuminuria. Conclusion: Considerable risk reductions for cardiovascular disease and mortality were seen with combined long-term risk factor improvement.

Keyword
Blood lipids, blood pressure, cardiovascular diseases, diabetes mellitus, HbA1c
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-298832 (URN)10.1177/1479164116637311 (DOI)000376973200003 ()27190080 (PubMedID)
Available from: 2016-07-11 Created: 2016-07-11 Last updated: 2017-11-28Bibliographically approved
Zethelius, B., Gudbjornsdottir, S., Eliasson, B., Eeg-Olofsson, K., Svensson, A.-M. & Cederholm, J. (2016). Electrical atrial vulnerability and renal complications in type 2 diabetes. Reply to Montaigne D, Coisne A, Sosner P et al [letter] [Letter to the editor]. Diabetologia, 59(4), 863-864.
Open this publication in new window or tab >>Electrical atrial vulnerability and renal complications in type 2 diabetes. Reply to Montaigne D, Coisne A, Sosner P et al [letter]
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2016 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 59, no 4, 863-864 p.Article in journal, Letter (Other academic) Published
Keyword
Albuminuria, Atrial fibrillation, Epidemiology, Longitudinal study design, Type 2 diabetes
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-296891 (URN)10.1007/s00125-016-3877-8 (DOI)000371802700026 ()26843077 (PubMedID)
Available from: 2016-07-05 Created: 2016-06-20 Last updated: 2017-11-28Bibliographically approved
Svennberg, E., Lindahl, B., Berglund, L., Eggers, K. M., Venge, P., Zethelius, B., . . . Hijazi, Z. (2016). NT-proBNP is a powerful predictor for incident atrial fibrillation: Validation of a multimarker approach. International Journal of Cardiology, 223, 74-81.
Open this publication in new window or tab >>NT-proBNP is a powerful predictor for incident atrial fibrillation: Validation of a multimarker approach
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2016 (English)In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 223, 74-81 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Biomarkers may be of value to identify individuals at risk of developing atrial fibrillation (AF). Using a multimarker approach, this study investigated if the biomarkers; NT-proBNP, high-sensitivity cardiac troponin (hs-cTn), growth differentiation factor-15 (GDF-15), cystatin C and high-sensitivity C-reactive protein (CRP) are independent predictors for incident AF.

METHODS: Blood samples were collected from 883 individuals in the Uppsala Longitudinal Study of Adult Men (ULSAM) and 978 individuals in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. Participants were followed for 10-13years with n=113 incident AF cases in ULSAM and n=148 in PIVUS. The associations between biomarkers and incident AF were analysed in Cox proportional hazards regression models.

RESULTS: The hazard ratio (HR) for incident AF was significant for all five biomarkers in unadjusted analyses in both cohorts. Only NT-proBNP remained significant when adjusting for cardiovascular risk factors and the other biomarkers (HR (1SD) 2.05 (1.62-2.59) (ULSAM) and 1.56 (1.30-1.86) (PIVUS), both p<0.001). The C-index improved from 0.64 to 0.69 in ULSAM and from 0.62 to 0.68 in PIVUS, by adding NT-proBNP to cardiovascular risk factors (both p<0.001). The C-index of the CHARGE-AF risk score increased from 0.62 to 0.68 (ULSAM) and 0.60 to 0.66 (PIVUS) by addition of NT-proBNP (p<0.001).

CONCLUSIONS: Using a multimarker approach NT-proBNP was the strongest predictor of incident AF in two cohorts, and improved risk prediction when added to traditional risk factors. NT-proBNP significantly improved the predictive ability of the novel CHARGE-AF risk score, although the predictive value remained modest.

National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-304095 (URN)10.1016/j.ijcard.2016.08.001 (DOI)000387036200029 ()27541645 (PubMedID)
Available from: 2016-10-02 Created: 2016-10-02 Last updated: 2017-11-30Bibliographically approved
Skoglund, P. H., Hoijer, J., Ärnlöv, J., Zethelius, B. & Svensson, P. (2015). Amino-Terminal Pro-B-Type Natriuretic Peptide Improves Discrimination for Incident Atherosclerotic Cardiovascular Disease Beyond Ambulatory Blood Pressure in Elderly Men. Hypertension, 66(3), 681-686.
Open this publication in new window or tab >>Amino-Terminal Pro-B-Type Natriuretic Peptide Improves Discrimination for Incident Atherosclerotic Cardiovascular Disease Beyond Ambulatory Blood Pressure in Elderly Men
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2015 (English)In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 66, no 3, 681-686 p.Article in journal (Refereed) Published
Abstract [en]

Improvement of risk prediction for atherosclerotic cardiovascular disease (ASCVD) is needed. Both ambulatory blood pressure (ABP) and biomarkers amino-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity C-reactive protein and cystatin C improve risk prediction but they have not been evaluated in relation to each other. We analyzed whether NT-proBNP, high-sensitivity C-reactive protein, or cystatin C improved risk prediction beyond traditional ASCVD risk factors combined with 24-hour systolic BP (SBP). Secondary aim was to evaluate whether ABP improved risk prediction when compared with models with the biomarkers. We followed up 907 70-year-old men, free of baseline disease, for incident ASCVD defined as fatal or nonfatal myocardial infarction or fatal or nonfatal stroke for a median of 10 years. Cox regression was used to estimate the association between variables in the models and incident ASCVD. Biomarkers were added to a model containing both traditional risk factors and ABP and the models were compared on C-statistics and net reclassification improvement. Twenty-four hour SBP improved discrimination for incident ASCVD when compared with office SBP in a traditional risk factor model (area under the receiver-operating characteristic curve, +2.4%). NT-proBNP further improved reclassification (+18.7%-19.9%; P<0.01) when added to ABP models, whereas high-sensitivity C-reactive protein and cystatin C did not. Twenty-four hour SBP significantly improved net reclassification when added to a traditional risk factor model that included NT-proBNP. The combination of 24-hour SBP and NT-proBNP improved discrimination and net reclassification for incident ASCVD when compared with office SBP in elderly men. NT-proBNP, but not high-sensitivity C-reactive protein or cystatin C, improved risk prediction and discrimination when added to a model that included ABP.

Keyword
aged, B-type natriuretic peptide, blood-brain barrier, blood pressure monitoring, ambulatory, C-reactive protein, cardiovascular diseases, cystatin c, longitudinal studies
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-261939 (URN)10.1161/HYPERTENSIONAHA.115.05717 (DOI)000359664700033 ()26150437 (PubMedID)
Funder
The Karolinska Institutet's Research Foundation
Available from: 2015-09-22 Created: 2015-09-07 Last updated: 2017-12-04Bibliographically approved
Zethelius, B. & Cederholm, J. (2015). Comparison between indexes of insulin resistance for risk prediction of cardiovascular diseases or development of diabetes. Diabetes Research and Clinical Practice, 110(2), 183-192.
Open this publication in new window or tab >>Comparison between indexes of insulin resistance for risk prediction of cardiovascular diseases or development of diabetes
2015 (English)In: Diabetes Research and Clinical Practice, ISSN 0168-8227, E-ISSN 1872-8227, Vol. 110, no 2, 183-192 p.Article in journal (Refereed) Published
Abstract [en]

Aim: The predictive effect of various insulin resistance indexes for risk of cardiovascular diseases (CVD) or type 2 diabetes (T2DM) is still unclear. Methods: One thousand and forty-nine 71-years-old male subjects from the Swedish ULSAM study, mean follow-up 9 years. All subjects performed the euglycemic insulin clamp for M/I [glucose disposal/mean insulin], and 75-g oral glucose tolerance test for Ceder-IR: 1/glucose uptake rate/[mean glucose x log mean insulin]; Matsuda-IR: 1/10,000/square root [glucose0 x insulin0 x glucose120 x insulin120]; Belfiore-IR: 1/([glucose0 + glucose120]/normal mean glucose x [insulin0 + insulin120]/normal mean insulin)+1); and HOMA-IR: [glucose0 x insulin0]/22.5. Results: Bland-Altman plots showed best agreement between M/I versus Belfiore-IR and Ceder-IR with mean difference near zero, -0.21 to -0.46, while -0.68 to -0.77 for the other indexes. ISI-Ceder was the strongest predictor for incident nonfatal/fatal ischemic heart disease (CHD) or CVD at Cox regression in all subjects, and for incident T2DM at logistic regression in 1024 subjects with no baseline T2DM, with significantly higher hazard ratios or odds ratios than with all other indexes, also with best model fit, after adjusting for clinical characteristics and the traditional cardiovascular risk factors, including metabolic syndrome for CVD risk. Conclusion: Ceder-IR performed strongest as independent predictor for incidences of CHD/CVD and T2DM.

Keyword
Myocardial infarction, Cardiovascular diseases, Diabetes mellitus, Insulin resistance, Insulin clamp test
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-272301 (URN)10.1016/j.diabres.2015.09.003 (DOI)000366317100010 ()
Available from: 2016-01-14 Created: 2016-01-13 Last updated: 2017-11-30Bibliographically approved
Ekström, N., Svensson, A.-M., Miftaraj, M., Andersson Sundell, K., Cederholm, J., Zethelius, B., . . . Gudbjörnsdottir, S. (2015). Durability of oral hypoglycemic agents in drug naïve patients with type 2 diabetes: report from the Swedish National Diabetes Register (NDR). BMJ open diabetes research & care, 3, Article ID e000059.
Open this publication in new window or tab >>Durability of oral hypoglycemic agents in drug naïve patients with type 2 diabetes: report from the Swedish National Diabetes Register (NDR)
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2015 (English)In: BMJ open diabetes research & care, ISSN 2052-4897, Vol. 3, e000059Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: To analyze the durability of monotherapy with different classes of oral hypoglycemic agents (OHAs) in drug naïve patients with type 2 diabetes mellitus (T2DM) in real life.

METHODS: Men and women with T2DM, who were new users of OHA monotherapy and registered in the Swedish National Diabetes Register July 2005-December 2011, were available (n=17 309) and followed for up to 5.5 years. Time to monotherapy failure, defined as discontinuation of continuous use with the initial agent, switch to a new agent, or add-on treatment of a second agent, was analyzed as a measure of durability. Baseline characteristics were balanced by propensity score matching 1:5 between groups of sulfonylurea (SU) versus metformin (n=4303) and meglitinide versus metformin (n=1308). HRs with 95% CIs were calculated using Cox regression models.

RESULTS: SU and meglitinide, as compared with metformin, were associated with increased risk of monotherapy failure (HR 1.74; 95% CI 1.56 to 1.94 and 1.66; 1.37 to 2.00 for SU and meglitinide, respectively). When broken down by type of monotherapy failure, SU and meglitinide were associated with an increased risk of add-on treatment of a second agent (HR 3.14; 95% CI 2.66 to 3.69 and 2.52; 1.89 to 3.37 for SU and meglitinide, respectively) and of switch to a new agent (HR 2.81; 95% CI 2.01 to 3.92 and 3.78; 2.25 to 6.32 for SU and meglitinide, respectively). The risk of discontinuation did not differ significantly between the groups.

CONCLUSIONS: In this nationwide observational study reflecting clinical practice, SU and meglitinide showed substantially increased risk of switch to a new agent or add on of a second agent compared with metformin. These results indicate superior glycemic durability with metformin compared with SU and also meglitinide in real life.

National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-268229 (URN)10.1136/bmjdrc-2014-000059 (DOI)25815205 (PubMedID)
Available from: 2015-12-03 Created: 2015-12-03 Last updated: 2015-12-04Bibliographically approved
Kehr, E., Batista, J., Zadra, G., Arthur, R., Grundmark, B., Zethelius, B., . . . Loda, M. (2015). Immunohistochemical Analysis of the AMPK Pathway in Prostate Cancer in the Context of the Metabolic Syndrome. Paper presented at 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology, MAR 21-27, 2015, Boston, MA. Laboratory Investigation, 95(S1), 233A-234A, Article ID 930.
Open this publication in new window or tab >>Immunohistochemical Analysis of the AMPK Pathway in Prostate Cancer in the Context of the Metabolic Syndrome
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2015 (English)In: Laboratory Investigation, ISSN 0023-6837, E-ISSN 1530-0307, Vol. 95, no S1, 233A-234A p., 930Article in journal, Meeting abstract (Other academic) Published
National Category
Other Medical Sciences not elsewhere specified
Identifiers
urn:nbn:se:uu:diva-247681 (URN)000348948001437 ()
Conference
104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology, MAR 21-27, 2015, Boston, MA
Available from: 2015-03-24 Created: 2015-03-23 Last updated: 2017-12-04Bibliographically approved
Kehr, E., Batista, J., Zadra, G., Arthur, R., Grundmark, B., Zethelius, B., . . . Loda, M. (2015). Immunohistochemical Analysis of the AMPK Pathway in Prostate Cancer in the Context of the Metabolic Syndrome. Paper presented at 104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology, MAR 21-27, 2015, Boston, MA. Modern Pathology, 28, 233A-234A.
Open this publication in new window or tab >>Immunohistochemical Analysis of the AMPK Pathway in Prostate Cancer in the Context of the Metabolic Syndrome
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2015 (English)In: Modern Pathology, ISSN 0893-3952, E-ISSN 1530-0285, Vol. 28, 233A-234A p.Article in journal, Meeting abstract (Other academic) Published
National Category
Other Medical Sciences not elsewhere specified
Identifiers
urn:nbn:se:uu:diva-249058 (URN)000349502201268 ()
Conference
104th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology, MAR 21-27, 2015, Boston, MA
Available from: 2015-04-20 Created: 2015-04-10 Last updated: 2017-12-04Bibliographically approved
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