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1.  Association Between Paradoxical HDL Cholesterol Decrease and Risk of Major Adverse Cardiovascular Events in Patients Initiated on Statin Treatment in a Primary Care Setting 
Clinical Drug Investigation  2015;36:225-233.
Background and Objectives
Statin-induced changes in high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) are unrelated. Many patients initiated on statins experience a paradoxical decrease in HDL-C. The aim of this study was to evaluate the association between a decrease in HDL-C and risk of major adverse cardiovascular events (MACE).
Data from 15,357 primary care patients initiated on statins during 2004–2009 were linked with data from mandatory national hospital, drug-dispensing, and cause-of-death registers, and were grouped according to HDL-C change: decreased ≥0.1 mmol/L, unchanged ±0.1 or ≥0.1 mmol/L increased. To evaluate the association between decrease in HDL-C and risk of MACE, a sample of propensity score-matched patients from the decreased and unchanged groups was created, using the latter group as reference. MACE was defined as myocardial infarction, unstable angina pectoris, ischaemic stroke, or cardiovascular mortality. Cox proportional hazards models were used to estimate relative risks.
HDL-C decreased in 20 %, was unchanged in 58%, and increased in 22 % of patients initiated on statin treatment (96 % treated with simvastatin). The propensity score-matched sample comprised 5950 patients with mean baseline HDL-C and LDL-C of 1.69 and 4.53 mmol/L, respectively. HDL-C decrease was associated with 56 % higher MACE risk (hazard ratio 1.56; 95 % confidence interval 1.12–2.16; p < 0.01) compared with the unchanged HDL-C group.
Paradoxical statin-induced reduction in HDL-C was relatively common and was associated with increased risk of MACE.
Electronic supplementary material
The online version of this article (doi:10.1007/s40261-015-0372-9) contains supplementary material, which is available to authorized users.
PMCID: PMC4761013  PMID: 26718960
2.  Time Trends in Incidence and Mortality of Acute Myocardial Infarction, and All-Cause Mortality following a Cardiovascular Prevention Program in Sweden 
PLoS ONE  2015;10(11):e0140201.
In 1988, a cardiovascular prevention program which combined an individual and a population-based strategy was launched within primary health-care in Sollentuna, a municipality in Stockholm County. The aim of this study was to investigate time trends in the incidence of and mortality from acute myocardial infarction and all-cause mortality in Sollentuna compared with the rest of Stockholm County during a period of two decades following the implementation of a cardiovascular prevention program.
Materials and Methods
The average population in Sollentuna was 56,589 (49% men) and in Stockholm County (Sollentuna included) 1,795,504 (49% men) during the study period of 1987–2010. Cases of hospitalized acute myocardial infarction and death were obtained for the population of Sollentuna and the rest of Stockholm County using national registries of hospital discharges and deaths. Acute myocardial infarction incidence and mortality were estimated using the average population of Sollentuna and Stockholm in 1987–2010.
During the observation period, the incidence of acute myocardial infarction decreased more in Sollentuna compared with the rest of Stockholm County in women (-22% vs. -7%; for difference in slope <0.05). There was a trend towards a greater decline in Sollentuna compared to the rest of Stockholm County in the incidence of acute myocardial infarction (in men), acute myocardial mortality, and all-cause mortality but the differences were not significant.
During a period of steep decline in acute myocardial infarction incidence and mortality in Stockholm County the municipality of Sollentuna showed a stronger trend in women possibly compatible with favorable influence of a cardiovascular prevention program.
Trial Registration NCT02212145
PMCID: PMC4651336  PMID: 26580968
3.  Prediagnostic serum glucose and lipids in relation to survival in breast cancer patients: a competing risk analysis 
BMC Cancer  2015;15:913.
Abnormal glucose and lipids levels may impact survival after breast cancer (BC) diagnosis, but their association to other causes of mortality such as cardiovascular (CV) disease may result in a competing risk problem.
We assessed serum glucose, triglycerides (TG) and total cholesterol (TC) measured prospectively 3 months to 3 years before diagnosis in 1798 Swedish women diagnosed with any type of BC between 1985 and 1999. In addition to using Cox regression, we employed latent class proportional hazards models to capture any heterogeneity of associations between these markers and BC death. The latter method was extended to include the primary outcome (BC death) and competing outcomes (CV death and death from other causes), allowing latent class-specific hazard estimation for cause-specific deaths.
A lack of association between prediagnostic glucose, TG or TC with BC death was observed with Cox regression. With latent class proportional hazards model, two latent classes (Class I and II) were suggested. Class I, comprising the majority (81.5 %) of BC patients, had an increased risk of BC death following higher TG levels (HR: 1.87, 95 % CI: 1.01–3.45 for every log TG increase). Lower overall survival was observed in Class II, but no association for BC death was found. On the other hand, TC positively corresponded to CV death in Class II, and similarly, glucose to death from other causes.
Addressing cohort heterogeneity in relation to BC survival is important in understanding the relationship between metabolic markers and cause-specific death in presence of competing outcomes.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-015-1928-z) contains supplementary material, which is available to authorized users.
PMCID: PMC4650114  PMID: 26577580
Breast cancer; Glucose; Lipid; Competing risk; Survival; Latent class
4.  Disability Pension at the Time of Coronary Revascularisation Is Associated with Higher Five-Year Mortality; A Swedish Nationwide, Register-Based Prospective Cohort Study 
PLoS ONE  2015;10(8):e0135277.
Although coronary revascularisation by coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) are common procedures, little is known regarding disability pension (DP) at the time of coronary revascularisation and its association with mortality. The aim was to investigate the five-year mortality following a first coronary revascularisation among women and men on DP, compared with those not on DP at the time of intervention, accounting for socio-demographic and medical factors.
Material and Methods
A nationwide prospective population-based cohort study was conducted, using national registers including 70,040 patients (80% men), aged 30–64 years, with a first CABG (n = 24,987; 36%) or PCI (n = 45,053; 64%) during 1994–2006 in Sweden, who were alive 30 days after the intervention. The main outcome was all-cause and cause-specific mortality within five years or through 31 December 2006, following CABG and PCI, and the exposure was DP at the time of a first coronary revascularisation. Information on DP, patient characteristics, date and cause of death was obtained from nationwide registers. Hazard ratios (HR) with 95% confidence intervals (CI) for the outcome were estimated, using Cox proportional hazard regression analyses. All analyses were stratified by type of intervention and gender.
Four percent died following coronary revascularisation. Cardiovascular disease was the most common cause of death (54%), followed by neoplasms (25%). Regardless of type of intervention, gender and after multivariable adjustments, patients on DP had a higher HR for five-year mortality compared with those not on DP at time of revascularisation (CABG: women HR 2.14; 95% CI 1.59–2.89, men HR 2.09; 1.84–2.38, PCI: women HR 2.25; 1.78–2.83, men HR 1.95; 1.72–2.21). Young women on DP at the time of PCI had a substantially higher HR (HR 4.10; 95% CI: 2.25–7.48).
Patients on DP at the time of first coronary revascularisation had a higher five-year risk of mortality compared with those not on DP.
PMCID: PMC4532455  PMID: 26261990
5.  Prevalence of All-Cause and Diagnosis-Specific Disability Pension at the Time of First Coronary Revascularisation: A Population-Based Swedish Cross-Sectional Study 
PLoS ONE  2015;10(1):e0115540.
Although coronary revascularisation by coronary artery bypass graft surgery (CABG) and percutaneous coronary intervention (PCI) is well documented, scientific knowledge on disability pension (DP) at the time of revascularisation is lacking. The aim was to investigate the prevalence of all-cause and diagnosis-specific DP at the time of a first coronary revascularisation, accounting for socio-demographic and medical factors.
Materials and Methods
A population-based cross-sectional study using Swedish registers was conducted including all 65,676 patients (80% men) who when aged 30–63 years, within 1994–2006, had a first CABG (n = 22,959) or PCI (n = 42,717) and did not have old-age pension. Associations between socio-demographic and medical factors and the probability of DP were estimated by odds ratios (OR) with 95% confidence intervals (CI) using logistic regression analyses.
The prevalence of DP at time of revascularisation was 24%, mainly due to musculoskeletal diagnoses. Sixty-two percent had had DP for at least four years before the revascularisation. In the multivariable analyses, DP was more common in women (OR: 2.40; 95% CI: 2.29–2.50), older patients (50–63 years); especially men aged 60–63 years with CABG (OR: 4.91; 95% CI: 4.27–5.66), lower educational level; especially men with PCI (OR: 2.96; 95% CI: 2.69–3.26), patients born outside Sweden; especially men with PCI (OR: 2.11; 95% CI: 1.96–2.27), and in women with an indication of other diagnoses than acute coronary syndrome (ACS) or stable angina pectoris for PCI (OR: 1.72; 95% CI: 1.31–2.24).
About a quarter had DP at the time of revascularisation, often due to musculoskeletal diagnoses. More than half had had DP for at least four years before the intervention. DP was associated with female gender, older age, lower educational level, and being born outside Sweden.
PMCID: PMC4309573  PMID: 25629517
6.  Fructosamine Is a Useful Indicator of Hyperglycaemia and Glucose Control in Clinical and Epidemiological Studies – Cross-Sectional and Longitudinal Experience from the AMORIS Cohort 
PLoS ONE  2014;9(10):e111463.
Fructosamine is a glycemic biomarker which may be useful for indication and control of diabetes respectively.
The objective of the study was to evaluate fructosamine as an indicator of hyperglycaemia and glucose control in subjects with diabetes.
Design, Setting & Patients
From the AMORIS cohort, subjects with serum glucose, fructosamine and HbA1c from the same examination were studied cross-sectionally and longitudinally (n = 10,987; 5,590 overnight-fasting). The guidelines of the American Diabetes Association were followed for classification of prediabetes and diabetes. Separate analyses were performed in patients with a newly detected or a known diagnosis of type 1 or type 2 diabetes respectively.
All three biomarkers were strongly correlated. With regard to the association between fructosamine and HbA1c Pearson linear correlation coefficients in the range of 0.67–0.75 were observed in fasting and non-fasting subjects with type 1 or type 2 diabetes. Analyses of glucose control in fasting patients with type 2 diabetes having all three biomarkers measured at three separate occasions within on average 290 days of the index examination showed similar trends over time for glucose, fructosamine and HbA1c. Discrimination of subjects with and without diabetes across the range of fructosamine levels was good (area under curve (AUC) 0.91–0.95) and a fructosamine level of 2.5 mmol/L classified subjects to diabetes with a sensitivity of 61% and a specificity of 97%.
Fructosamine is closely associated with HbA1c and glucose respectively and may be a useful biomarker of hyperglycaemia and glucose control in clinical and epidemiological studies.
PMCID: PMC4213035  PMID: 25353659
7.  Serum calcium and risk of gastrointestinal cancer in the Swedish AMORIS study 
BMC Public Health  2013;13:663.
Observational studies have indicated that high calcium intake may prevent colorectal cancer, but as for randomized trials the results are inconclusive. Meanwhile, limited data on the link between serum calcium and cancer risk is available. We investigated the relation between serum calcium and risk of different gastrointestinal cancers in a prospective study.
A cohort based on 492,044 subjects with baseline information on calcium (mmol/L) and albumin (g/L) was selected from the Swedish Apolipoprotein MOrtality RISk (AMORIS) study. Multivariable Cox proportional hazard models were used to analyse associations between standardised levels, quartiles and age/sex-specific categories of serum calcium and risk of oesophageal, stomach, colon, rectal cancer and also colorectal cancer combined, while taking into account serum albumin and other comorbidities.
During 12 years of follow-up, we identified 323 incident oesophageal cancers, 782 stomach cancers, 2519 colon cancers, and 1495 rectal cancers. A positive association was found between albumin-adjusted serum calcium and risk of oesophageal [HR: 4.82 (95% CI: 2.07 – 11.19) for high compared to normal age-specific calcium levels] and colon cancer [e.g. HR: 1.07 (95% CI: 1.00 – 1.14) for every SD increase of calcium] as well as colorectal cancer [e.g. HR: 1.06 (95% CI: 1.02-1.11) for every SD increase of calcium] in women. In men there were similar but weaker non-statistically significant trends.
The positive relation between serum calcium, oesophageal cancer and colorectal cancer calls for further studies including calcium regulators to evaluate whether there is a true link between calcium metabolism and development of gastrointestinal cancer.
PMCID: PMC3729677  PMID: 23866097
Gastrointestinal cancer; Calcium; Albumin
8.  Inorganic phosphate and the risk of cancer in the Swedish AMORIS study 
BMC Cancer  2013;13:257.
Both dietary and serum levels of inorganic phosphate (Pi) have been linked to development of cancer in experimental studies. This is the first population-based study investigating the relation between serum Pi and risk of cancer in humans.
From the Swedish Apolipoprotein Mortality Risk (AMORIS) study, we selected all participants (> 20 years old) with baseline measurements of serum Pi, calcium, alkaline phosphatase, glucose, and creatinine (n = 397,292). Multivariable Cox proportional hazards regression analyses were used to assess serum Pi in relation to overall cancer risk. Similar analyses were performed for specific cancer sites.
We found a higher overall cancer risk with increasing Pi levels in men ( HR: 1.02 (95% CI: 1.00-1.04) for every SD increase in Pi), and a negative association in women (HR: 0.97 (95% CI: 0.96-0.99) for every SD increase in Pi). Further analyses for specific cancer sites showed a positive link between Pi quartiles and the risk of cancer of the pancreas, lung, thyroid gland and bone in men, and cancer of the oesophagus, lung, and nonmelanoma skin cancer in women. Conversely, the risks for developing breast and endometrial cancer as well as other endocrine cancer in both men and women were lower in those with higher Pi levels.
Abnormal Pi levels are related to development of cancer. Furthermore, the in verse association between Pi levels and risk of breast, endometrial and other endocrine cancers may indicate the role of hormonal factors in the relation between Pi metabolism and cancer.
PMCID: PMC3664604  PMID: 23706176
Cancer; Inorganic phosphate; Prospective cohort study
9.  Iron metabolism and risk of cancer in the Swedish AMORIS study 
Cancer Causes & Control  2013;24(7):1393-1402.
Pre-clinical studies have shown that iron can be carcinogenic, but few population-based studies investigated the association between markers of the iron metabolism and risk of cancer while taking into account inflammation. We assessed the link between serum iron (SI), total-iron binding capacity (TIBC), and risk of cancer by levels of C-reactive protein (CRP) in a large population-based study (n = 220,642).
From the Swedish Apolipoprotein Mortality Risk (AMORIS) study, we selected all participants (>20 years old) with baseline measurements of serum SI, TIBC, and CRP. Multivariate Cox proportional hazards regression was carried out for standardized and quartile values of SI and TIBC. Similar analyses were performed for specific cancers (pancreatic, colon, liver, respiratory, kidney, prostate, stomach, and breast cancer). To avoid reverse causation, we excluded those with follow-up <3 years.
We found a positive association between standardized TIBC and overall cancer [HR 1.03 (95 % CI 1.01–1.05)]. No statistically significant association was found between SI and cancer risk except for postmenopausal breast cancer [HR for standardized SI 1.09 (95 % CI 1.02–1.15)]. The association between TIBC and specific cancer was only statistically significant for colon cancer [i.e., HR for standardized TIBC: 1.17 (95 % CI 1.08–1.28)]. A borderline interaction between SI and levels of CRP was observed only in stomach cancer.
As opposed to pre-clinical findings for serum iron and cancer, this population-based epidemiological study showed an inverse relation between iron metabolism and cancer risk. Minimal role of inflammatory markers observed warrants further study focusing on developments of specific cancers.
PMCID: PMC3675271  PMID: 23649231
Cancer; C-reactive protein; Iron; Iron-binding capacity; Sweden
10.  Serum Glucose and Fructosamine in Relation to Risk of Cancer 
PLoS ONE  2013;8(1):e54944.
Impaired glucose metabolism has been linked with increased cancer risk, but the association between serum glucose and cancer risk remains unclear. We used repeated measurements of glucose and fructosamine to get more insight into the association between the glucose metabolism and risk of cancer.
We selected 11,998 persons (>20 years old) with four prospectively collected serum glucose and fructosamine measurements from the Apolipoprotein Mortality Risk (AMORIS) study. Multivariate Cox proportional hazards regression was used to assess standardized log of overall mean glucose and fructosamine in relation to cancer risk. Similar analyses were performed for tertiles of glucose and fructosamine and for different types of cancer.
A positive trend was observed between standardized log overall mean glucose and overall cancer risk (HR = 1.08; 95% CI: 1.02–1.14). Including standardized log fructosamine in the model resulted in a stronger association between glucose and cancer risk and aninverse association between fructosamine and cancer risk (HR = 1.17; 95% CI: 1.08–1.26 and HR: 0.89; 95% CI: 0.82–0.96, respectively). Cancer risks were highest among those in the highest tertile of glucose and lowest tertile of fructosamine. Similar findings were observed for prostate, lung, and colorectal cancer while none observed for breast cancer.
The contrasting effect between glucose, fructosamine, and cancer risk suggests the existence of distinct groups among those with impaired glucose metabolism, resulting in different cancer risks based on individual metabolic profiles. Further studies are needed to clarify whether glucose is a proxy of other lifestyle-related or metabolic factors.
PMCID: PMC3556075  PMID: 23372798
11.  Gamma-glutamyl transferase and C-reactive protein as alternative markers of metabolic abnormalities and their associated comorbidites: a prospective cohort study 
Background: Recent studies suggested that gamma-glutamyl transferase (GGT) and C-reactive protein (CRP) are good markers of metabolic abnormalities. We assessed the link between GGT, CRP and common metabolic abnormalities, as well their link to related diseases, such as cancer and cardiovascular disease (CVD). Methods: We selected 333,313 subjects with baseline measurements of triglycerides (TG), total cholesterol (TC), glucose, GGT and CRP in the Swedish AMORIS study. Baseline measurement of BMI was available for 63,900 persons and 77,944 had baseline measurements of HDL. Pearson correlation coefficients between CRP, GGT, and metabolic components (TG, HDL, BMI and TC) were calculated. To investigate the combined effect of GGT and CRP we created a score ranging from 0 to 6 and used Cox proportional hazard models to evaluate its association with CVD and cancer. Results: 21,216 individuals developed cancer and 47,939 CVD. GGT and TG had the strongest correlation (r=0.22). An increased risk of cancer was identified with elevated levels of GGT or CRP or both markers (GGT-CRP score ≥3); the greatest risk of cancer was found when GGT-CRP score = 6 (HR: 1.40 (95%CI: 1.31-1.48) and 1.60 (1.47-1.76) compared to GGT-CRP score = 0, respectively). Conclusion: While GGT and CRP have been shown to be associated with metabolic abnormalities previously, their association to the components investigated in this study was limited. Results did demonstrate that these markers were predictive of associated diseases, such as cancer.
PMCID: PMC3508539  PMID: 23205179
GGT; CRP; metabolic abnormalities; cardiovascular disease; cancer
12.  Serum Lipids and the Risk of Gastrointestinal Malignancies in the Swedish AMORIS Study 
Journal of Cancer Epidemiology  2012;2012:792034.
Background. Metabolic syndrome has been linked to an increased cancer risk, but the role of dyslipidaemia in gastrointestinal malignancies is unclear. We aimed to assess the risk of oesophageal, stomach, colon, and rectal cancers using serum levels of lipid components. Methods. From the Swedish Apolipoprotein Mortality Risk (AMORIS) study, we selected 540,309 participants (> 20 years old) with baseline measurements of total cholesterol (TC), triglycerides (TG), and glucose of whom 84,774 had baseline LDL cholesterol (LDL), HDL cholesterol (HDL), apolipoprotein B (apoB), and apolipoprotein A-I (apoA-I). Multivariate Cox proportional hazards regression was used to assess glucose and lipid components in relation to oesophageal, stomach, colon, and rectal cancer risk. Results. An increased risk of oesophageal cancer was observed in persons with high TG (e.g. HR: 2.29 (95% CI: 1.42–3.68) for the 4th quartile compared to the 1st) and low LDL, LDL/HDL ratio, TC/HDL ratio, log (TG/HDL), and apoB/apoA-I ratio. High glucose and TG were linked with an increased colon cancer risk, while high TC levels were associated with an increased rectal cancer risk. Conclusion. The persistent link between TC and rectal cancer risk as well as between TG and oesophageal and colon cancer risk in normoglycaemic individuals may imply their substantiality in gastrointestinal carcinogenesis.
PMCID: PMC3437288  PMID: 22969802
13.  Sickness Absence following Coronary Revascularisation. A National Study of Women and Men of Working Age in Sweden 1994–2006 
PLoS ONE  2012;7(7):e40952.
Evidence based and gender specific knowledge about sickness absence following coronary revascularisation is lacking. The objective was to investigate sickness absence after a first coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) among women and men in a national Swedish study.
Materials and Methods
All patients 30–63 years of age, who underwent a first CABG (n = 22,985, 16% women) or PCI (40,891, 22% women) in Sweden between 1994 and 2006 were included. Information on sickness absence, co-morbidity, and other patient characteristics was obtained from national registers. Long-term sickness absence (LTSA) was defined as >180 and >90 sick-leave days in the first sick-leave spell following CABG and PCI, respectively. Prevalence ratio (PR) and 95% confidence interval (CI) of LTSA were calculated.
LTSA followed the interventions in 41% and 36% for CABG and PCI patients, respectively. Women had more often LTSA compared with men, (CABG PR = 1.23: 95% CI 1.19–1.28 and PCI PR = 1.19; 95% CI 1.16–1.23). A history of sickness absence the year before the intervention increased the risk for LTSA after the intervention in both genders. Among women, older age, or being self employed or unemployed was associated with a lower risk for LTSA. Among men previous cardiovascular disease, diabetes and low socio-economic position increased the risk. During the observation period, there was no change in sickness absence rates among PCI patients but an increase among CABG patients adjusting for patient characteristics.
This national study covering a 13-year period shows that long-term sickness absence following coronary revascularisation is common in Sweden, especially among women, and is associated with socio-economic position, co-morbidity, and sickness absence during the year before the intervention. Gender specific scientific knowledge about use and effects of sickness absence following coronary revascularisation is warranted for the patients, the treating physicians, the healthcare sector, and the society.
PMCID: PMC3404085  PMID: 22848415
14.  Lipid profiles and the risk of endometrial cancer in the Swedish AMORIS study 
While the association between obesity and endometrial cancer (EC) is well established, the underlying mechanisms require further study. We assessed possible links between lipid profiles and EC risk, while also taking into account BMI, parity, and menopausal status at baseline.
Using the information available from the Swedish Apolipoprotein MOrtality RISk (AMORIS) study we created a cohort of 225,432 women with baseline values for glucose, triglycerides (TG), and total cholesterol (TC). Two subgroups of 31,792 and 26,317 had, in addition, baseline measurements of HDL, LDL, apolipoprotein A-I and apoB and BMI, respectively. We used Multivariate Cox proportional hazards models to analyze quartiles and dichotomized values of these lipid components for a link to EC risk.
During mean follow-up of 12 years (SD: 4.15), 1,144 persons developed endometrial cancer. A statistically significant association was found between TG and EC risk when using both quartiles and a clinical cut-off (Hazard Ratio (HR): 1.10 (95%CI: 0.88-1.37), 1.34 (1.09-1.63), and 1.57 (1.28-1.92)) for the 2nd, 3rd, and 4th quartile, compared to the 1st, with P-value for trend: <0.001). The association remained after exclusion of the first three years of follow-up. Also total cholesterol and TG/HDL ratio were positively associated with EC risk, but no link was found for the other lipid components studied.
This detailed analysis of lipid components showed a consistent relation between TG levels and EC risk. Future research should continue to analyze the metabolic pathway and its relation to EC risk, as a pathway to further understand the relation of obesity and disease.
PMCID: PMC3376923  PMID: 22724049
Lipid profiles; risk factor; endometrial cancer; Swedish AMORIS study
15.  Biomarker-based score to predict mortality in persons aged 50 years and older: a new approach in the Swedish AMORIS study 
Management of frailty is the cornerstone of geriatric medicine, but there remains a need to identify biomarkers that can predict early death, and thereby lead to effective clinical interventions. We aimed to study the combination of C-reactive protein (CRP), albumin, gamma-glutamyl transferase (GGT), and HDL to predict mortality.
A total of 44,457 persons aged 50+ whose levels of CRP, albumin, GGT, and HDL were measured at baseline were selected from the Swedish Apolipoprotein MOrtality RISk (AMORIS) study. A mortality score, ranging from 0 to 4, was created by adding the number of markers with abnormal values according to the clinical cut-off (CRP > 10 mg/L, albumin < 35 mg/L, GGT > 36 kU/L, HDL < 1.04 mmol/L). Mortality was studied with multivariate Cox proportional hazards models.
2,245 persons died from cancer, 3,276 from circulatory disease, and 1,860 from other causes. There was a positive trend between mortality score and all-cause mortality as well as cancer and circulatory disease-specific death (e.g. HR for all-cause mortality: 1.39 (95%CI: 1.32-1.46), 2.04 (1.89-2.21), and 3.36 (2.87-3.93), for score=1, 2, and 3+, compared to score=0). Among cancer patients with no other co-morbidities (n=1,955), there was a positive trend between the score and mortality (HR: 1.24 (95%CI: 1.0.-1.49), 2.38 (95%CI: 1.76-3.22), and 5.47 (95%CI: 2.98-10.03) for score=1, 2, and 3+ compared to score=0).
By combining biomarkers of different mechanisms contributing to patient frailty, we found a strong marker for mortality in persons aged 50+. Elevated risks among cancer patients with no other co-morbidities prior to biomarker assessment call for validation in other cohorts and testing of different combinations and cut-offs than those used here, in order to aid decision-making in treatment of older cancer patients.
PMCID: PMC3316450  PMID: 22493753
Frailty; mortality; albumin; HDL-cholesterol; C-reactive protein; gamma-glutamyltransferase
16.  Association between levels of C-reactive protein and leukocytes and cancer: Three repeated measurements in the Swedish AMORIS study 
To study levels of C-reactive protein (CRP) and leukocytes, as inflammatory markers, in the context of cancer risk.
From the Apolipoprotein MOrtality RISk (AMORIS) study, we selected 102,749 persons with one measurement and 9,273 persons with three repeated measurements of CRP and leukocytes. Multivariate Cox proportional hazards regression was applied to categories of CRP (<10, 10-15, 15-25, 25-50, >50 g/L) and quartiles of leukocytes. An Inflammation-based Predictive Score (IPS) indicated whether someone had CRP levels >10mg/L combined with leukocytes >10×109/L. Reverse causality was assessed by excluding those with <3, 5, or 7 years of follow-up. To analyze repeated measurements of CRP and leukocytes the repeated IPS (IPSr) was calculated by adding the IPS of each measurement.
In the cohort with one measurement, there was a positive trend between CRP and cancer, with the lowest category being the reference: 0.99 (0.92-1.06), 1.28 (1.11-1.47), 1.27 (1.09-1.49), 1.22 (1.01-1.48) for the 2nd to 5th categories, respectively. This association disappeared when excluding those with follow-up <3, 5 or 7 years. The association between leukocytes and cancer was slightly stronger. In the cohort with repeated measurements the IPSr was strongly associated with cancer risk: 1.87 (1.33-2.63), 1.51 (0.56-4.06), 4.46 (1.43-13.87) for IPSr =1, 2, and 3, compared to IPSr =0. The association remained after excluding those with follow-up <1 year.
Conclusions and impact
Our large prospective cohort study adds evidence for a link between inflammatory markers and cancer risk by using repeated measurements and ascertaining reverse causality.
PMCID: PMC3078551  PMID: 21297038
cancer; C-reactive protein; leukocytes; Sweden
17.  Incidence of cancer among Nordic airline pilots over five decades: occupational cohort study 
BMJ : British Medical Journal  2002;325(7364):567.
To assess the incidence of cancer among male airline pilots in the Nordic countries, with special reference to risk related to cosmic radiation.
Retrospective cohort study, with follow up of cancer incidence through the national cancer registries.
Denmark, Finland, Iceland, Norway, and Sweden.
10 032 male airline pilots, with an average follow up of 17 years.
Main outcome measures
Standardised incidence ratios, with expected numbers based on national cancer incidence rates; dose-response analysis using Poisson regression.
466 cases of cancer were diagnosed compared with 456 expected. The only significantly increased standardised incidence ratios were for skin cancer: melanoma 2.3 (95% confidence interval 1.7 to 3.0), non-melanoma 2.1 (1.7 to 2.8), basal cell carcinoma 2.5 (1.9 to 3.2). The relative risk of skin cancers increased with the estimated radiation dose. The relative risk of prostate cancer increased with increasing number of flight hours in long distance aircraft.
This study does not indicate a marked increase in cancer risk attributable to cosmic radiation, although some influence of cosmic radiation on skin cancer cannot be entirely excluded. The suggestion of an association between number of long distance flights (possibly related to circadian hormonal disturbances) and prostate cancer needs to be confirmed.
What is already known on this topicAirline pilots are occupationally exposed to cosmic radiation and other potentially carcinogenic elementsIn the studies published so far, dose-response patterns have not been characterisedWhat this study addsNo marked risk of cancer attributable to cosmic radiation is observed in airline pilotsA threefold excess of skin cancers is seen among pilots with longer careers, but the influence of recreational exposure to ultraviolet light cannot be quantifiedA slight increase in risk of prostate cancer with increasing number of long haul flights suggests a need for more studies on the effects of circadian hormonal disturbances
PMCID: PMC124549  PMID: 12228131

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