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1.  Lipid profiles and the risk of endometrial cancer in the Swedish AMORIS study 
Background
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.
Methods
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.
Results
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.
Conclusion
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
2.  Ability of a biomarker-based score to predict death from circulatory disease and cancer in NHANES III 
BMC Public Health  2012;12:895.
Background
A score based on serum concentrations of C-reactive protein (CRP), albumin, gamma-glutamyl transferase (GGT), and HDL cholesterol was positively associated with death from cancer, circulatory disease, and all-cause mortality. We replicated this in the third National Health and Nutrition Examination Survey (NHANES III), a US nationally representative survey conducted between 1988–1994.
Methods
Baseline measurements of CRP, albumin, GGT, and HDL were available for participants with mortality follow-up (n=13,056). A biomarker score, ranging 0–4, was created by adding number of markers with abnormal values (cut-off: CRP>10mg/L, albumin<35mg/L, GGT>36U/L, HDL<1.04mmol/L). Its association with mortality was analyzed with multivariate Cox proportional hazards models.
Results
The score was positively associated with death from all causes, cancer and circulatory disease [e.g. HR all-cause mortality: 1.21 (95% CI: 1.09, 1.35), 1.92 (1.67, 2.20), 3.38 (2.62, 4.36), and 7.93 (5.77, 10.89), for score 1, 2, 3, 4 vs.0]. These patterns were found across the Charlson Comorbidity Index (CCI). Where CCI =3, risk of cancer death was 1.09 (0.93, 1.28), 1.81 (1.43, 2.29), 4.67 (3.05, 7.14), and 6.97 (5.32, 9.14) for score 1, 2, 3, 4 vs. 0. No effect-modification by sex or race/ethnicity was observed.
Conclusions
These findings correlate with results from a Swedish study. This biomarker-based score could help clinicians make decisions in prevention and disease management.
doi:10.1186/1471-2458-12-895
PMCID: PMC3549794  PMID: 23092358
Mortality; Albumin; HDL-cholesterol; C-reactive protein; Gamma-glutamyltransferase
3.  Association between levels of C-reactive protein and leukocytes and cancer: Three repeated measurements in the Swedish AMORIS study 
Objective
To study levels of C-reactive protein (CRP) and leukocytes, as inflammatory markers, in the context of cancer risk.
Methods
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.
Results
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.
doi:10.1158/1055-9965.EPI-10-1190
PMCID: PMC3078551  PMID: 21297038
cancer; C-reactive protein; leukocytes; Sweden
4.  Serum calcium and risk of gastrointestinal cancer in the Swedish AMORIS study 
BMC Public Health  2013;13:663.
Background
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1186/1471-2458-13-663
PMCID: PMC3729677  PMID: 23866097
Gastrointestinal cancer; Calcium; Albumin
5.  Biomarker Profiling by Nuclear Magnetic Resonance Spectroscopy for the Prediction of All-Cause Mortality: An Observational Study of 17,345 Persons 
PLoS Medicine  2014;11(2):e1001606.
In this study, Würtz and colleagues conducted high-throughput profiling of blood specimens in two large population-based cohorts in order to identify biomarkers for all-cause mortality and enhance risk prediction. The authors found that biomarker profiling improved prediction of the short-term risk of death from all causes above established risk factors. However, further investigations are needed to clarify the biological mechanisms and the utility of these biomarkers to guide screening and prevention.
Please see later in the article for the Editors' Summary
Background
Early identification of ambulatory persons at high short-term risk of death could benefit targeted prevention. To identify biomarkers for all-cause mortality and enhance risk prediction, we conducted high-throughput profiling of blood specimens in two large population-based cohorts.
Methods and Findings
106 candidate biomarkers were quantified by nuclear magnetic resonance spectroscopy of non-fasting plasma samples from a random subset of the Estonian Biobank (n = 9,842; age range 18–103 y; 508 deaths during a median of 5.4 y of follow-up). Biomarkers for all-cause mortality were examined using stepwise proportional hazards models. Significant biomarkers were validated and incremental predictive utility assessed in a population-based cohort from Finland (n = 7,503; 176 deaths during 5 y of follow-up). Four circulating biomarkers predicted the risk of all-cause mortality among participants from the Estonian Biobank after adjusting for conventional risk factors: alpha-1-acid glycoprotein (hazard ratio [HR] 1.67 per 1–standard deviation increment, 95% CI 1.53–1.82, p = 5×10−31), albumin (HR 0.70, 95% CI 0.65–0.76, p = 2×10−18), very-low-density lipoprotein particle size (HR 0.69, 95% CI 0.62–0.77, p = 3×10−12), and citrate (HR 1.33, 95% CI 1.21–1.45, p = 5×10−10). All four biomarkers were predictive of cardiovascular mortality, as well as death from cancer and other nonvascular diseases. One in five participants in the Estonian Biobank cohort with a biomarker summary score within the highest percentile died during the first year of follow-up, indicating prominent systemic reflections of frailty. The biomarker associations all replicated in the Finnish validation cohort. Including the four biomarkers in a risk prediction score improved risk assessment for 5-y mortality (increase in C-statistics 0.031, p = 0.01; continuous reclassification improvement 26.3%, p = 0.001).
Conclusions
Biomarker associations with cardiovascular, nonvascular, and cancer mortality suggest novel systemic connectivities across seemingly disparate morbidities. The biomarker profiling improved prediction of the short-term risk of death from all causes above established risk factors. Further investigations are needed to clarify the biological mechanisms and the utility of these biomarkers for guiding screening and prevention.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
A biomarker is a biological molecule found in blood, body fluids, or tissues that may signal an abnormal process, a condition, or a disease. The level of a particular biomarker may indicate a patient's risk of disease, or likely response to a treatment. For example, cholesterol levels are measured to assess the risk of heart disease. Most current biomarkers are used to test an individual's risk of developing a specific condition. There are none that accurately assess whether a person is at risk of ill health generally, or likely to die soon from a disease. Early and accurate identification of people who appear healthy but in fact have an underlying serious illness would provide valuable opportunities for preventative treatment.
While most tests measure the levels of a specific biomarker, there are some technologies that allow blood samples to be screened for a wide range of biomarkers. These include nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry. These tools have the potential to be used to screen the general population for a range of different biomarkers.
Why Was This Study Done?
Identifying new biomarkers that provide insight into the risk of death from all causes could be an important step in linking different diseases and assessing patient risk. The authors in this study screened patient samples using NMR spectroscopy for biomarkers that accurately predict the risk of death particularly amongst the general population, rather than amongst people already known to be ill.
What Did the Researchers Do and Find?
The researchers studied two large groups of people, one in Estonia and one in Finland. Both countries have set up health registries that collect and store blood samples and health records over many years. The registries include large numbers of people who are representative of the wider population.
The researchers first tested blood samples from a representative subset of the Estonian group, testing 9,842 samples in total. They looked at 106 different biomarkers in each sample using NMR spectroscopy. They also looked at the health records of this group and found that 508 people died during the follow-up period after the blood sample was taken, the majority from heart disease, cancer, and other diseases. Using statistical analysis, they looked for any links between the levels of different biomarkers in the blood and people's short-term risk of dying. They found that the levels of four biomarkers—plasma albumin, alpha-1-acid glycoprotein, very-low-density lipoprotein (VLDL) particle size, and citrate—appeared to accurately predict short-term risk of death. They repeated this study with the Finnish group, this time with 7,503 individuals (176 of whom died during the five-year follow-up period after giving a blood sample) and found similar results.
The researchers carried out further statistical analyses to take into account other known factors that might have contributed to the risk of life-threatening illness. These included factors such as age, weight, tobacco and alcohol use, cholesterol levels, and pre-existing illness, such as diabetes and cancer. The association between the four biomarkers and short-term risk of death remained the same even when controlling for these other factors.
The analysis also showed that combining the test results for all four biomarkers, to produce a biomarker score, provided a more accurate measure of risk than any of the biomarkers individually. This biomarker score also proved to be the strongest predictor of short-term risk of dying in the Estonian group. Individuals with a biomarker score in the top 20% had a risk of dying within five years that was 19 times greater than that of individuals with a score in the bottom 20% (288 versus 15 deaths).
What Do These Findings Mean?
This study suggests that there are four biomarkers in the blood—alpha-1-acid glycoprotein, albumin, VLDL particle size, and citrate—that can be measured by NMR spectroscopy to assess whether otherwise healthy people are at short-term risk of dying from heart disease, cancer, and other illnesses. However, further validation of these findings is still required, and additional studies should examine the biomarker specificity and associations in settings closer to clinical practice. The combined biomarker score appears to be a more accurate predictor of risk than tests for more commonly known risk factors. Identifying individuals who are at high risk using these biomarkers might help to target preventative medical treatments to those with the greatest need.
However, there are several limitations to this study. As an observational study, it provides evidence of only a correlation between a biomarker score and ill health. It does not identify any underlying causes. Other factors, not detectable by NMR spectroscopy, might be the true cause of serious health problems and would provide a more accurate assessment of risk. Nor does this study identify what kinds of treatment might prove successful in reducing the risks. Therefore, more research is needed to determine whether testing for these biomarkers would provide any clinical benefit.
There were also some technical limitations to the study. NMR spectroscopy does not detect as many biomarkers as mass spectrometry, which might therefore identify further biomarkers for a more accurate risk assessment. In addition, because both study groups were northern European, it is not yet known whether the results would be the same in other ethnic groups or populations with different lifestyles.
In spite of these limitations, the fact that the same four biomarkers are associated with a short-term risk of death from a variety of diseases does suggest that similar underlying mechanisms are taking place. This observation points to some potentially valuable areas of research to understand precisely what's contributing to the increased risk.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001606
The US National Institute of Environmental Health Sciences has information on biomarkers
The US Food and Drug Administration has a Biomarker Qualification Program to help researchers in identifying and evaluating new biomarkers
Further information on the Estonian Biobank is available
The Computational Medicine Research Team of the University of Oulu and the University of Bristol have a webpage that provides further information on high-throughput biomarker profiling by NMR spectroscopy
doi:10.1371/journal.pmed.1001606
PMCID: PMC3934819  PMID: 24586121
6.  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
7.  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.
doi:10.1155/2012/792034
PMCID: PMC3437288  PMID: 22969802
8.  Iron metabolism and risk of cancer in the Swedish AMORIS study 
Cancer Causes & Control  2013;24(7):1393-1402.
Objectives
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).
Methods
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.
Results
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.
Conclusions
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.
doi:10.1007/s10552-013-0219-8
PMCID: PMC3675271  PMID: 23649231
Cancer; C-reactive protein; Iron; Iron-binding capacity; Sweden
9.  Inorganic phosphate and the risk of cancer in the Swedish AMORIS study 
BMC Cancer  2013;13:257.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/1471-2407-13-257
PMCID: PMC3664604  PMID: 23706176
Cancer; Inorganic phosphate; Prospective cohort study
10.  The ratio of CRP to prealbumin levels predict mortality in patients with hospital-acquired acute kidney injury 
BMC Nephrology  2011;12:30.
Background
Animal and human studies suggest that inflammation and malnutrition are common in acute kidney injury (AKI) patients. However, only a few studies reported CRP, a marker of inflammation, albumin, prealbumin and cholesterol, markers of nutritional status were associated with the prognosis of AKI patients. No study examined whether the combination of inflammatory and nutritional markers could predict the mortality of AKI patients.
Methods
155 patients with hospital-acquired AKI were recruited to this prospective cohort study according to RIFLE (Risk, Injury, Failure, Lost or End Stage Kidney) criteria. C-reactive protein (CRP), and the nutritional markers (albumin, prealbumin and cholesterol) measured at nephrology consultation were analyzed in relation to all cause mortality of these patients. In addition, CRP and prealbumin were also measured in healthy controls (n = 45), maintenance hemodialysis (n = 70) and peritoneal dialysis patients (n = 50) and then compared with AKI patients.
Results
Compared with healthy controls and end-stage renal disease patients on maintenance hemodialysis or peritoneal dialysis, patients with AKI had significantly higher levels of CRP/prealbumin (p < 0.001). Higher level of serum CRP and lower levels of albumin, prealbumin and cholesterol were found to be significant in the patients with AKI who died within 28 days than those who survived >28 days. Similarly, the combined factors including the ratio of CRP to albumin (CRP/albumin), CRP/prealbumin and CRP/cholesterol were also significantly higher in the former group (p < 0.001 for all). Multivariate analysis (Cox regression) revealed that CRP/prealbumin was independently associated with mortality after adjustment for age, gender, sepsis and sequential organ failure assessment (SOFA, p = 0.027) while the others (CRP, albumin, prealbumin, cholesterol, CRP/albumin and CRP/cholesterol) became non-significantly associated. The hazard ratio was 1.00 (reference), 1.85, 2.25 and 3.89 for CRP/prealbumin increasing according to quartiles (p = 0.01 for the trend).
Conclusions
Inflammation and malnutrition were common in patients with AKI. Higher level of the ratio of CRP to prealbumin was associated with mortality of AKI patients independent of the severity of illness and it may be a valuable addition to SOFA score to independent of the severity of illness and it may be a valuable addition to SOFA score to predict the prognosis of AKI patients.
doi:10.1186/1471-2369-12-30
PMCID: PMC3142490  PMID: 21714897
inflammation; malnutrition; CRP; prealbumin; acute kidney injury
11.  Combined Impact of Health Behaviours and Mortality in Men and Women: The EPIC-Norfolk Prospective Population Study 
PLoS Medicine  2008;5(1):e12.
Background
There is overwhelming evidence that behavioural factors influence health, but their combined impact on the general population is less well documented. We aimed to quantify the potential combined impact of four health behaviours on mortality in men and women living in the general community.
Methods and Findings
We examined the prospective relationship between lifestyle and mortality in a prospective population study of 20,244 men and women aged 45–79 y with no known cardiovascular disease or cancer at baseline survey in 1993–1997, living in the general community in the United Kingdom, and followed up to 2006. Participants scored one point for each health behaviour: current non-smoking, not physically inactive, moderate alcohol intake (1–14 units a week) and plasma vitamin C >50 mmol/l indicating fruit and vegetable intake of at least five servings a day, for a total score ranging from zero to four. After an average 11 y follow-up, the age-, sex-, body mass–, and social class–adjusted relative risks (95% confidence intervals) for all-cause mortality(1,987 deaths) for men and women who had three, two, one, and zero compared to four health behaviours were respectively, 1.39 (1.21–1.60), 1.95 (1.70–-2.25), 2.52 (2.13–3.00), and 4.04 (2.95–5.54) p < 0.001 trend. The relationships were consistent in subgroups stratified by sex, age, body mass index, and social class, and after excluding deaths within 2 y. The trends were strongest for cardiovascular causes. The mortality risk for those with four compared to zero health behaviours was equivalent to being 14 y younger in chronological age.
Conclusions
Four health behaviours combined predict a 4-fold difference in total mortality in men and women, with an estimated impact equivalent to 14 y in chronological age.
From a large prospective population study, Kay-Tee Khaw and colleagues estimate the combined impact of four behaviors--not smoking, not being physically inactive, moderate alcohol intake, and at least five vegetable servings a day--amounts to 14 additional years of life.
Editors' Summary
Background.
Every day, or so it seems, new research shows that some aspect of lifestyle—physical activity, diet, alcohol consumption, and so on—affects health and longevity. For the person in the street, all this information is confusing. What is a healthy diet, for example? Although there are some common themes such as the benefit of eating plenty of fruit and vegetables, the details often differ between studies. And exactly how much physical activity is needed to improve health? Is a gentle daily walk sufficient or simply a stepping stone to doing enough exercise to make a real difference? The situation with alcohol consumption is equally confusing. Small amounts of alcohol apparently improve health but large amounts are harmful. As a result, it can be hard for public-health officials to find effective ways to encourage the behavioral changes that the scientific evidence suggests might influence the health of populations.
Why Was This Study Done?
There is another factor that is hindering official attempts to provide healthy lifestyle advice to the public. Although there is overwhelming evidence that individual behavioral factors influence health, there is very little information about their combined impact. If the combination of several small differences in lifestyle could be shown to have a marked effect on the health of populations, it might be easier to persuade people to make behavioral changes to improve their health, particularly if those changes were simple and relatively easy to achieve. In this study, which forms part of the European Prospective Investigation into Cancer and Nutrition (EPIC), the researchers have examined the relationship between lifestyle and the risk of dying using a health behavior score based on four simply defined behaviors—smoking, physical activity, alcohol drinking, and fruit and vegetable intake.
What Did the Researchers Do and Find?
Between 1993 and 1997, about 20,000 men and women aged 45–79 living in Norfolk UK, none of whom had cancer or cardiovascular disease (heart or circulation problems), completed a health and lifestyle questionnaire, had a health examination, and had their blood vitamin C level measured as part of the EPIC-Norfolk study. A health behavior score of between 0 and 4 was calculated for each participant by giving one point for each of the following healthy behaviors: current non-smoking, not physically inactive (physical inactivity was defined as having a sedentary job and doing no recreational exercise), moderate alcohol intake (1–14 units a week; a unit of alcohol is half a pint of beer, a glass of wine, or a shot of spirit), and a blood vitamin C level consistent with a fruit and vegetable intake of at least five servings a day. Deaths among the participants were then recorded until 2006. After allowing for other factors that might have affected their likelihood of dying (for example, age), people with a health behavior score of 0 were four times as likely to have died (in particular, from cardiovascular disease) than those with a score of 4. People with a score of 2 were twice as likely to have died.
What Do These Findings Mean?
These findings indicate that the combination of four simply defined health behaviors predicts a 4-fold difference in the risk of dying over an average period of 11 years for middle-aged and older people. They also show that the risk of death (particularly from cardiovascular disease) decreases as the number of positive health behaviors increase. Finally, they can be used to calculate that a person with a health score of 0 has the same risk of dying as a person with a health score of 4 who is 14 years older. These findings need to be confirmed in other populations and extended to an analysis of how these combined health behaviors affect the quality of life as well as the risk of death. Nevertheless, they strongly suggest that modest and achievable lifestyle changes could have a marked effect on the health of populations. Armed with this information, public-health officials should now be in a better position to encourage behavior changes likely to improve the health of middle-aged and older people.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050012.
The MedlinePlus encyclopedia contains a page on healthy living (in English and Spanish)
The MedlinePlus page on seniors' health contains links to many sites dealing with healthy lifestyles and longevity (in English and Spanish)
The European Prospective Investigation into Cancer and Nutrition (EPIC) study is investigating the relationship between nutrition and lifestyle and the development of cancer and other chronic diseases; information about the EPIC-Norfolk study is also available
The US Centers for Disease Control and Prevention provides information on healthy aging for older adults, including information on health-related behaviors (in English and Spanish)
The UK charity Age Concerns provides a fact sheet about staying healthy in later life
The London Health Observatory, which provides information for policy makers and practitioners about improving health and health care, has a section on how lifestyle and behavior affect health
doi:10.1371/journal.pmed.0050012
PMCID: PMC2174962  PMID: 18184033
12.  Obese frailty, physical performance deficits, and falls in older men with biochemical recurrence of prostate cancer on androgen deprivation therapy: a case-control study 
Urology  2011;77(4):934-940.
Objectives
Early androgen deprivation therapy (ADT) has no proven survival advantage in older men with biochemical recurrence (BCR) of prostate cancer (PCa), and it may contribute to geriatric frailty; we tested this hypothesis.
Methods
We conducted a case-control study of men aged 60+ with BCR on ADT (n=63) versus PCa survivors without recurrence (n=71). Frailty prevalence, “obese” frailty, Short Physical Performance Battery (SPPB) scores and falls were compared. An exploratory analysis of frailty biomarkers (CRP, ESR, hemoglobin, albumin, and total cholesterol) was performed. Summary statistics, univariate and multivariate regression analyses were conducted.
Results
More patients on ADT were obese (BMI >30; 46.2% vs. 20.6%; p=0.03). There were no statistical differences in SPPB (p=0.41) or frailty (p=0.20). Using a proposed “obese” frailty criteria, 8.7% in ADT group were frail and 56.5% were “prefrail”, compared with 2.9% and 48.8% of controls (p=0.02). Falls in the last year were higher in ADT group (14.3% vs. 2.8%; p=0.02). In analyses controlling for age, clinical characteristics, and comorbidities, the ADT group trended toward significance for “obese” frailty (p = 0.14) and falls (OR = 4.74, p = 0.11). Comorbidity significantly increased the likelihood of “obese” frailty (p=0.01) and falls (OR 2.02, p = 0.01).
Conclusions
Men with BCR on ADT are frailer using proposed modified “obese” frailty criteria. They may have lower performance status and more falls. A larger, prospective trial is necessary to establish a causal link between ADT use and progression of frailty and disability.
doi:10.1016/j.urology.2010.11.024
PMCID: PMC3074039  PMID: 21269665
prostate cancer; biochemical recurrence; androgen deprivation therapy; frailty; older adults
13.  The Association of CHA2DS2-VASc Score and Blood Biomarkers with Ischemic Stroke Outcomes: The Belgrade Stroke Study 
PLoS ONE  2014;9(9):e106439.
Background
Many blood biomarkers have a positive association with stroke outcome, but adding blood biomarkers to the National Institutes of Health Stroke Scale (NIHSS) did not significantly improve its discriminatory ability. We investigated the association of the CHA2DS2-VASc score with unfavourable functional outcome (defined as a 30-day modified Rankin Scale [mRS] ≥3) in patients presenting with acute ischemic stroke (AIS), and examined whether the addition of blood biomarkers (troponin I [TnI], fibrinogen, C-reactive protein [CRP]) affects the model discriminatory ability.
Methods
We conducted an observational single-centre study of consecutive patients with AIS. All patients were admitted to hospital within 24 hours from the neurological symptoms onset.
Results
Of 240 patients (mean age 70.0±8.9 years), unfavourable 30-day outcome occurred in 92 (38.3%). Patients with mRS≥3 were older and more likely to have atrial fibrillation or other comorbidities (all p<0.001). They had higher levels of CRP, fibrinogen, TnI and higher CHA2DS2-VASc and CHADS2 scores (all p<0.05). The adjusted CHA2DS2-VASc score had excellent predictive ability for poor stroke outcome (c-statistic 0.982;95%CI,0.964–1.000, p<0.001). Whilst CRP had the highest sensitivity (83.7%), cardiac TnI was the most specific (97.3%) for prediction of poor stroke outcome (cut-off: >0.09µg/L). Compared with each of these biomarkers, CHA2DS2-VASc score had significantly better predictive ability for poor stroke outcome (c-statistic for CRP, Fibrinogen and TnI was 0.853;95%CI,0.802–0.895, 0.848;95%CI,0.796–0.891, and 0.792;95%CI,0.736–0.842, all p<0.001, respectively, versus 0.932;95%CI,0.892–0.960, p<0.001 for the CHA2DS2-VASc, all p for the comparisons<0.01). There was no significant difference in the predictive ability of the CHA2DS2-VASc score vs. combinations of the CHA2DS2-VASc and TnI or TnI, fibrinogen and CRP (z statistic 0.369, p = 0.7119; integrated discrimination index 0.00801 and 0.00172, respectively, both p>0.05).
Conclusions
The CHA2DS2-VASc score alone reliably predicts 30-day unfavourable outcome of stroke. Adding blood biomarkers to the CHA2DS2-VASc score did not significantly increase the predictive ability of the model.
doi:10.1371/journal.pone.0106439
PMCID: PMC4153640  PMID: 25184809
14.  Serum γ-glutamyltranspeptidase predicts all-cause, cardiovascular and liver mortality in older adults 
Background
Serum γ-glutamyltranspeptidase (GGT), a marker of fatty liver disease (FLD), predicts mortality in young adults. However, the association between serum GGT and mortality in older adults is unclear.
Objectives
To examine if elevated serum GGT predicts all-cause, cardiovascular (CVD), and liver mortality in community-dwelling older adults.
Design and setting
A prospective cohort study including 2364 participants (mean-age 70 yr, BMI-24.5 kg/m2, 54% women) from the Rancho Bernardo Study who attended a research visit in 1984–87 when multiple metabolic covariates were ascertained including serum GGT. They were followed for a mean (± standard deviation) of 13.7 (±6.2) years.
Measurement
Multivariable-adjusted Cox-proportional hazards analyses were conducted to examine the association between elevated serum GGT (>51 U/L in men and > 33 U/L in women) and all-cause, CVD, and liver mortality.
Results
In these older men and women, cumulative mortality was 56.2% (n=1329) with CVD and liver mortality accounting for 49.4% and 2.3% of all deaths, respectively, over 32,387 person-years of follow-up. In multivariate analyses (adjusted for age, sex, alcohol use, body-mass-index, total cholesterol, HDL cholesterol, serum triglyceride, smoking status, systolic blood pressure, diabetes mellitus, serum interleukin-6, and c-reactive protein), serum GGT elevation was significantly associated with all-cause (HR, 1.55, 95% CI, 1.21–1.98), CVD (HR, 1.51, 95% CI, 1.04–2.17), and liver mortality (HR, 9.10, 95% CI, 3.42–24.26).
Conclusions
In community-dwelling older adults, serum GGT is an independent predictor of all-cause, CVD, and liver mortality.
PMCID: PMC3940213  PMID: 23997501
NAFLD; GGT; and death
15.  Serum γ-glutamyltranspeptidase predicts all-cause, cardiovascular and liver mortality in older adults 
Background
Serum γ-glutamyltranspeptidase (GGT), a marker of fatty liver disease (FLD), predicts mortality in young adults. However, the association between serum GGT and mortality in older adults is unclear.
Objectives
To examine if elevated serum GGT predicts all-cause, cardiovascular (CVD), and liver mortality in community-dwelling older adults.
Design and setting
A prospective cohort study including 2364 participants (mean-age 70 yr, BMI-24.5 kg/m2, 54% women) from the Rancho Bernardo Study who attended a research visit in 1984–87 when multiple metabolic covariates were ascertained including serum GGT. They were followed for a mean (± standard deviation) of 13.7 (±6.2) years.
Measurement
Multivariable-adjusted Cox-proportional hazards analyses were conducted to examine the association between elevated serum GGT (>51 U/L in men and > 33 U/L in women) and all-cause, CVD, and liver mortality.
Results
In these older men and women, cumulative mortality was 56.2% (n=1329) with CVD and liver mortality accounting for 49.4% and 2.3% of all deaths, respectively, over 32,387 person-years of follow-up. In multivariate analyses (adjusted for age, sex, alcohol use, body-mass-index, total cholesterol, HDL cholesterol, serum triglyceride, smoking status, systolic blood pressure, diabetes mellitus, serum interleukin-6, and c-reactive protein), serum GGT elevation was significantly associated with all-cause (HR, 1.55, 95% CI, 1.21–1.98), CVD (HR, 1.51, 95% CI, 1.04–2.17), and liver mortality (HR, 9.10, 95% CI, 3.42–24.26).
Conclusions
In community-dwelling older adults, serum GGT is an independent predictor of all-cause, CVD, and liver mortality.
PMCID: PMC3940213  PMID: 23997501
NAFLD; GGT; and death
16.  The relationship between the presence and site of cancer, an inflammation-based prognostic score and biochemical parameters. Initial results of the Glasgow Inflammation Outcome Study 
British Journal of Cancer  2010;103(6):870-876.
Background:
Cancer incidence is increasing in the United Kingdom, as well as on a global basis. Biochemical parameters, such as C-reactive protein and albumin (combined to form the modified Glasgow Prognostic Score, mGPS), alkaline phosphatase (Alk phos), γ-glutamyl transferase (GGT) and serum calcium have been reported to be associated with cancer and non-cancer mortality. Therefore, to definitively examine the interrelationships between the above biochemical parameters, the mGPS and the presence of cancer, the Glasgow Inflammation Outcome Study was undertaken. The aim of this initial study was to examine the effect of cancer on markers of systemic inflammation induced by the liver (mGPS) and on levels of routine biochemical parameters.
Methods:
Patients (n=223 303) who had a single incidental sample taken for C-reactive protein, albumin, calcium and serum liver function tests where available, between 2000 and 2008 were studied. Those with a pathological diagnosis of cancer (n=22 715) were identified. The mGPS was constructed and liver function tests classified in accordance with the local reference ranges.
Results:
Patients with cancer had higher C-reactive protein and lower albumin levels (and thus a higher mGPS), higher adjusted calcium, Alk phos and GGT levels, but lower aspartate transaminase (AST) and alanine transaminase (ALT) levels (all P<0.001). The strongest associations (Spearman's correlation ⩾0.3) in both the non-cancer and cancer groups were found between albumin, C-reactive protein and Alk phos, AST and ALT, AST and GGT and ALT and GGT (all P<0.001). On multivariate analysis, the associations with the presence of cancer remained with age, deprivation, C-reactive protein, albumin, adjusted calcium, Alk phos and GGT (all P<0.01). Patients following a diagnosis of cancer had lower albumin levels and thus higher mGPS (all P<0.001). Also, post-diagnosis patients were more likely to have lower adjusted calcium, bilirubin, Alk Phos, AST, ALT and GGT levels (all P<0.05). When the cancer diagnoses were ranked from those with the lowest proportion of mGPS 1 or 2 to those with the highest, the percentage of cases with a mGPS of 1 or 2 ranged from 21% in breast cancer to 46% in prostate cancer and to 68% in pulmonary cancer. Compared with breast cancer the mGPS was significantly higher in those diagnosed with dermatological, bladder, endocrinological, gynaecological, prostate, musculoskeletal, gastroesophageal, haematological, renal, colorectal, head and neck, pancreaticobiliary and pulmonary cancers (all P<0.001).
Conclusion:
The results of the present study indicate that the systemic inflammatory response is common in a large patient cohort, increased by the presence of cancer and associated with the perturbation of a number of biochemical parameters previously reported to be associated with mortality. There is a striking parallel between the proportions of cases with a mGPS of 1 or 2 and reported survival rates in these tumours.
doi:10.1038/sj.bjc.6605855
PMCID: PMC2966631  PMID: 20717110
C-reactive protein; albumin; adjusted calcium; liver function tests
17.  C-reactive protein as a predictor of mortality in patients affected with severe sepsis in intensive care unit 
Background
Severe sepsis is a primary cause of morbidity and mortality in the intensive care unit (ICU). Numerous biomarkers have been assessed to predict outcome and CRP is widely used. However, the relevance for mortality risk of the CRP level and the day when it is measured have not been well studied. We aimed to assess whether initial and/or third dayCRP values are as good predictors of mortality in ICU patients with severe sepsis as other well-known complex predictors of mortality, i.e., SOFA scores.
Methods
An observational cohort study was performed in a 20-bed respiratory ICU in a chest disease center. Patients with severe sepsis due to respiratory disease were enrolled in the study. SOFA scores, CRP values on admission and on the third day of hospital stay, and mortality rate were recorded. ROC curves for SOFA scores and CRP values were calculated.
Results
The study included 314 ICU patients with sepsis admitted between January 2009 and March 2010. The mortality rate was 14.2% (n = 45). The area under the curve (AUC) for CRP values and SOFA scores on admission and on the 3rd day in ICU were calculated as 0.57 (CI: 0.48-0.66); 0.72 (CI: 0.63-0.80); 0.72 (CI: 0.64-0.81); and 0.76 (CI: 0.67-0.86), respectively. Sepsis due to nosocomial infection, a CRP value > 100 mg/L and higher SOFA scores on 3rd day, were found to be risk factors for mortality (odds ratio [OR]: 3.76, confidence interval [CI]: 1.68-8.40, p < 0.001, OR: 2.70, CI: 1.41-2.01, p < 0.013, and OR: 1.68, CI: 1.41-2.01, p < 0.0001, respectively).
Conclusions
The risk of sepsis related mortality appears to be increased when the 3rd day CRP value is greater than 100 mg/dL. Thus, CRP appears to be as valuable a predictor of mortality as the SOFA score.
doi:10.1186/2049-6958-7-47
PMCID: PMC3529702  PMID: 23171626
Intensive care unit; Severe sepsis; Serum CRP follow up; SOFA score
18.  Reduced Glomerular Filtration Rate and Its Association with Clinical Outcome in Older Patients at Risk of Vascular Events: Secondary Analysis 
PLoS Medicine  2009;6(1):e1000016.
Background
Reduced glomerular filtration rate (GFR) is associated with increased cardiovascular risk in young and middle aged individuals. Associations with cardiovascular disease and mortality in older people are less clearly established. We aimed to determine the predictive value of the GFR for mortality and morbidity using data from the 5,804 participants randomized in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER).
Methods and Findings
Glomerular filtration rate was estimated (eGFR) using the Modification of Diet in Renal Disease equation and was categorized in the ranges ([20–40], [40–50], [50–60]) ≥ 60 ml/min/1.73 m2. Baseline risk factors were analysed by category of eGFR, with and without adjustment for other risk factors. The associations between baseline eGFR and morbidity and mortality outcomes, accrued after an average of 3.2 y, were investigated using Cox proportional hazard models adjusting for traditional risk factors. We tested for evidence of an interaction between the benefit of statin treatment and baseline eGFR status. Age, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, C-reactive protein (CRP), body mass index, fasting glucose, female sex, histories of hypertension and vascular disease were associated with eGFR (p = 0.001 or less) after adjustment for other risk factors. Low eGFR was independently associated with risk of all cause mortality, vascular mortality, and other noncancer mortality and with fatal and nonfatal coronary and heart failure events (hazard ratios adjusted for CRP and other risk factors (95% confidence intervals [CIs]) for eGFR < 40 ml/min/1.73m2 relative to eGFR ≥ 60 ml/min/1.73m2 respectively 2.04 (1.48–2.80), 2.37 (1.53–3.67), 3.52 (1.78–6.96), 1.64 (1.18–2.27), 3.31 (2.03–5.41). There were no nominally statistically significant interactions (p < 0.05) between randomized treatment allocation and eGFR for clinical outcomes, with the exception of the outcome of coronary heart disease death or nonfatal myocardial infarction (p = 0.021), with the interaction suggesting increased benefit of statin treatment in subjects with impaired GFRs.
Conclusions
We have established that, in an elderly population over the age of 70 y, impaired GFR is associated with female sex, with presence of vascular disease, and with levels of other risk factors that would be associated with increased risk of vascular disease. Further, impaired GFR is independently associated with significant levels of increased risk of all cause mortality and fatal vascular events and with composite fatal and nonfatal coronary and heart failure outcomes. Our analyses of the benefits of statin treatment in relation to baseline GFR suggest that there is no reason to exclude elderly patients with impaired renal function from treatment with a statin.
Using data from the PROSPER trial, Ian Ford and colleagues investigate whether reduced glomerular filtration rate is associated with cardiovascular and mortality risk among elderly people.
Editors' Summary
Background.
Cardiovascular disease (CVD)—disease that affects the heart and/or the blood vessels—is a common cause of death in developed countries. In the USA, for example, the single leading cause of death is coronary heart disease, a CVD in which narrowing of the heart's blood vessels slows or stops the blood supply to the heart and eventually causes a heart attack. Other types of CVD include stroke (in which narrowing of the blood vessels interrupts the brain's blood supply) and heart failure (a condition in which the heart can no longer pump enough blood to the rest of the body). Many factors increase the risk of developing CVD, including high blood pressure (hypertension), high blood cholesterol, having diabetes, smoking, and being overweight. Tools such as the “Framingham risk calculator” assess an individual's overall CVD risk by taking these and other risk factors into account. CVD risk can be minimized by taking drugs to reduce blood pressure or cholesterol levels (for example, pravastatin) and by making lifestyle changes.
Why Was This Study Done?
Another potential risk factor for CVD is impaired kidney (renal) function. In healthy people, the kidneys filter waste products and excess fluid out of the blood. A reduced “estimated glomerular filtration rate” (eGFR), which indicates impaired renal function, is associated with increased CVD in young and middle-aged people and increased all-cause and cardiovascular death in people who have vascular disease. But is reduced eGFR also associated with CVD and death in older people? If it is, it would be worth encouraging elderly people with reduced eGFR to avoid other CVD risk factors. In this study, the researchers determine the predictive value of eGFR for all-cause and vascular mortality (deaths caused by CVD) and for incident vascular events (a first heart attack, stroke, or heart failure) using data from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). This clinical trial examined pravastatin's effects on CVD development among 70–82 year olds with pre-existing vascular disease or an increased risk of CVD because of smoking, hypertension, or diabetes.
What Did the Researchers Do and Find?
The trial participants were divided into four groups based on their eGFR at the start of the study. The researchers then investigated the association between baseline CVD risk factors and baseline eGFR and between baseline eGFR and vascular events and deaths that occurred during the 3-year study. Several established CVD risk factors were associated with a reduced eGFR after allowing for other risk factors. In addition, people with a low eGFR (between 20 and 40 units) were twice as likely to die from any cause as people with an eGFR above 60 units (the normal eGFR for a young person is 100 units; eGFR decreases with age) and more than three times as likely to have nonfatal coronary heart disease or heart failure. A low eGFR also increased the risk of vascular mortality, other noncancer deaths, and fatal coronary heart disease and heart failure. Finally, pravastatin treatment reduced coronary heart disease deaths and nonfatal heart attacks most effectively among participants with the greatest degree of eGFR impairment.
What Do These Findings Mean?
These findings suggest that, in elderly people, impaired renal function is associated with levels of established CVD risk factors that increase the risk of vascular disease. They also suggest that impaired kidney function increases the risk of all-cause mortality, fatal vascular events, and fatal and nonfatal coronary heat disease and heart failure. Because the study participants were carefully chosen for inclusion in PROSPER, these findings may not be generalizable to all elderly people with vascular disease or vascular disease risk factors. Nevertheless, increased efforts should probably be made to encourage elderly people with reduced eGFR and other vascular risk factors to make lifestyle changes to reduce their overall CVD risk. Finally, although the effect of statins in elderly patients with renal dysfunction needs to be examined further, these findings suggest that this group of patients should benefit at least as much from statins as elderly patients with healthy kidneys.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000016.
The MedlinePlus Encyclopedia has pages on coronary heart disease, stroke, and heart failure (in English and Spanish)
MedlinePlus provides links to many other sources of information on heart disease, vascular disease, and stroke (in English and Spanish)
The US National Institute of Diabetes and Digestive and Kidney Diseases provides information on how the kidneys work and what can go wrong with them, including a list of links to further information about kidney disease
The American Heart Association provides information on all aspects of cardiovascular disease for patients, caregivers, and professionals (in several languages)
More information about PROSPER is available on the Web site of the Vascular Biochemistry Department of the University of Glasgow
doi:10.1371/journal.pmed.1000016
PMCID: PMC2628400  PMID: 19166266
19.  Egy-Score Predicts Severe Hepatic Fibrosis and Cirrhosis in Egyptians With Chronic Liver Diseases: A Pilot Study 
Hepatitis Monthly  2013;13(6):e10810.
Background
Non-invasive methods for assessment of hepatic fibrosis are increasingly needed. Recent studies showed that combined elevation of tumor markers CA 19-9 and CA 125 is predictive of severe hepatic fibrosis or cirrhosis with high specificity.
Objectives
We aimed at developing a new panel of surrogate biomarkers for prediction of the stage of hepatic fibrosis by combining tumor markers with other known biomarkers of hepatic fibrosis.
Patients and Methods
A total of 92 patients with different types of chronic liver diseases (chronic hepatitis B, chronic hepatitis C and autoimmune hepatitis), were prospectively enrolled in our cohort. They were subjected to: ALT, AST, GGT, ALP, total bilirubin, INR, total cholesterol, albumin, platelet count, cancer antigen 19-9 (CA 19-9), cancer antigen 125 (CA 125), cancer antigen 15-3 (CA 15-3), haptoglobin, alpha-2-macroglobulin, apolipoprotein A1, abdominal ultrasound, liver biopsy and histological staging of hepatic fibrosis using the METAVIR system.
Results
Combined elevation of CA 19-9 and CA 125 with a summated value > 37 U/mL is predictive of severe hepatic fibrosis or cirrhosis (stage F3-F4 METAVIR) with a probability of 77.6%. Multivariate analysis showed that the most relevant collection of biomarkers for prediction of stage of hepatic fibrosis is: CA 19-9, age, alpha-2- macroglobulin, total bilirubin, platelet count & albumin. We developed a new score, named the “Egy-Score”, using a regression equation composed of this panel of biomarkers. Egy-Score could differentiate no or early fibrosis (stage F0-F2 METAVIR) from severe fibrosis or cirrhosis (stage F3-F4 METAVIR) with 83.7% accuracy.
Conclusions
Non-invasive assessment of hepatic fibrosis could be done using the Egy-Score. Egy-Score could differentiate no or early fibrosis (stage F0-F2 METAVIR) from severe fibrosis or cirrhosis (stage F3 - F4 METAVIR) with 83.7% accuracy.
doi:10.5812/hepatmon.10810
PMCID: PMC3773216  PMID: 24046790
Alpha-Macroglobulins; CA-19-9 Antigen; Biological Markers; Fibrosis; Liver Cirrhosis
20.  Comprehensive Analysis of Common Serum Liver Enzymes as Prospective Predictors of Hepatocellular Carcinoma in HBV Patients 
PLoS ONE  2012;7(10):e47687.
Background
Serum liver enzymes are frequently tested in clinics to aid disease diagnosis. Large observational studies indicated that these enzymes might predict cancer risk and mortality. However, no prospective study has reported on their relationships with the risk of HBV-related hepatocellular carcinoma (HCC).
Methodology/Principal Findings
We evaluated the predictive values of four routinely tested liver enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [ALP], and gamma-glutamyltransferase [GGT]) in HCC risk in a prospectively enrolled clinical cohort of 588 Korean American HBV patients. For all four enzymes, the baseline level as well as the average and maximum levels during the first 1 or 2 years of follow-up were analyzed using multivariate Cox proportional hazards model. Patients were categorized into a normal or an elevated group based on the clinical cut-off of each enzyme. During a median follow-up of 7.5 years, 52 patients (incidence rate, 8.8%) developed HCC. The incidence rates were higher in the elevated groups for all four enzymes. The most significant finding was for GGT, with the highest incidence rate of 16.4% in the elevated group compared to 4.6% in the normal group (P<0.001). Compared to patients with normal baseline GGT, those with elevated GGT exhibited a significantly increased HCC risk with a hazards ratio (HR) of 2.60 (95% confidence interval [CI], 1.41–4.77, P = 0.002). Further analyses revealed a cumulative effect between baseline GGT and ALP (HR = 3.41, 95% CI 1.54–7.56, P = 0.003).
Conclusions Significance
Serum GGT might predict HCC risk in HBV patients individually or jointly with other enzymes.
doi:10.1371/journal.pone.0047687
PMCID: PMC3480412  PMID: 23112834
21.  Consumption of red meat and whole-grain bread in relation to biomarkers of obesity, inflammation, glucose metabolism and oxidative stress 
European Journal of Nutrition  2012;52(1):337-345.
Purpose
To examine the association of red meat and whole-grain bread consumption with plasma levels of biomarkers related to glucose metabolism, oxidative stress, inflammation and obesity.
Methods
Our cross-sectional study was based on 2,198 men and women who were selected as a sub-cohort for an investigation of biological predictors of diabetes and cardiovascular diseases from the European Prospective Investigation into Cancer and Nutrition-Potsdam study. Circulating levels of glycated hemoglobin, adiponectin, hs-CRP, gamma-glutamyltransferase, alanine-aminotransferase, fetuin-A, HDL-cholesterol and triglycerides were measured from random blood samples. Diet and lifestyle data were assessed by questionnaires, and anthropometric data were measured.
Results
After multivariable adjustment, higher consumption of whole-grain bread was significantly (P trend <0.05) associated with lower levels of GGT, ALT and hs-CRP, whereas higher consumption of red meat was significantly associated with higher levels of GGT and hs-CRP when adjusted for potential confounding factors related to lifestyle and diet. Further adjustment for body mass index and waist circumference attenuated the association between red meat and hs-CRP (P = 0.19).
Conclusions
The results of this study suggest that high consumption of whole-grain bread is related to lower levels of GGT, ALT and hs-CRP, whereas high consumption of red meat is associated with higher circulating levels of GGT and hs-CRP.
doi:10.1007/s00394-012-0340-6
PMCID: PMC3549403  PMID: 22426755
Red meat; Whole grain; Biomarkers; Glucose metabolism
22.  Biomarkers of inflammation and malnutrition associated with early death in healthy elderly people 
Objectives
To determine whether malnutrition and inflammation biomarkers predict all-cause, cancer and cardiovascular mortality in healthy elderly subjects.
Design
Prospective cohort.
Setting
Population-based study, Sète, French Mediterranean coast.
Participants
553 men and 888 women aged 60+ years from the POLA (Pathologies Oculaires Liées à l’Age) cohort, free of known co-morbidities.
Measurements
Plasma levels of cholesterol, albumin, transthyretin (TTR), C-reactive protein (CRP) and alpha 1-acid glycoprotein (AAG) were measured at baseline. To investigate the risks of 5-year (early) and 5–9 year (late) mortality hazard ratios (HR) were evaluated using Cox models.
Results
In men, the early death risk was increased for high CRP and AAG and for low albumin and TTR. In women, early death was associated with high AAG, low TTR and cholesterol. For late death, the only significant association was with CRP in men. A synergistic effect was observed between biomarkers of inflammation and malnutrition. The adjusted HR of early death was 4.98(95% Confidence Interval(CI)= 2.25–11.01) for both CRP in the highest quartile and albumin in the lowest in men. This risk was increased for AAG in the highest quartile and TTR in the lowest in men and women with an HR of 6.86(95%CI= 3.20–14.71) and 4.64(95%CI= 1.79–12.05) respectively. Cancer mortality was increased for high CRP and AAG and for low albumin and TTR in men but not in women.
Conclusions
Biomarkers of inflammation and malnutrition together predict early mortality. In healthy elderly subjects TTR and AAG could be helpful in identifying elderly subjects at higher risk of death.
doi:10.1111/j.1532-5415.2008.01677.x
PMCID: PMC2683250  PMID: 18410327
Age Factors; Aged; Aged, 80 and over; C-Reactive Protein; metabolism; Cardiovascular Diseases; immunology; mortality; Cause of Death; Cholesterol; blood; Female; Follow-Up Studies; France; Health Surveys; Humans; Inflammation Mediators; blood; Male; Middle Aged; Neoplasms; immunology; mortality; Orosomucoid; metabolism; Prealbumin; metabolism; Proportional Hazards Models; Prospective Studies; Protein-Energy Malnutrition; diagnosis; immunology; mortality; Reference Values; Risk Assessment; Serum Albumin; metabolism; Sex Factors
23.  Frailty and risk in proximal aortic surgery 
Objectives
Although frailty has recently been examined in various populations as a predictor of morbidity and mortality, its effect on thoracic aortic surgery outcomes has not been studied. The objective of the present study was to evaluate the role of frailty in predicting postoperative morbidity and mortality in patients undergoing proximal aortic replacement surgery.
Methods
A retrospective analysis of a prospectively maintained database was performed for all patients undergoing elective and nonelective proximal aortic operations (root, ascending aorta, and/or arch) at a single-referral institution from June 2005 to December 2012. A total of 581 patients underwent proximal aortic surgery, of whom 574 (98.8%) were included in the present analysis; 7 were excluded because of incomplete data. Frailty was evaluated using an index consisting of age > 70 years, body mass index < 18.5 kg/m2, anemia, history of stroke, hypoalbuminemia, and total psoas volume in the bottom quartile of the population. One point was given for each criterion met to determine a frailty score of 0 to 6. Frailty was defined as a score of ≥ 2. Risk models for length of stay > 14 days, discharge to other than home, 30-day composite major morbidity, 30-day composite major morbidity/mortality, and 30-day and 1-year mortality were calculated using multivariate regression modeling.
Results
Of the 574 patients, 148 (25.7%) were defined as frail (frailty score ≥ 2). The unadjusted 30-day/in-hospital and long-term outcomes were significantly worse for the frail versus nonfrail patients in all but 1 of the outcomes analyzed; no difference was found in the 30-day readmission rates between the 2 groups. In the multivariate model, a frailty score of ≥ 2 was associated with discharge to other than home and 30-day and 1-year mortality.
Conclusions
Frailty, as defined using a 6-component frailty index, can serve as an independent predictor of discharge disposition and early and late mortality risk in patients undergoing proximal aortic surgery. These frailty markers, all of which are easily assessed preoperatively, could provide valuable information for patient counseling and risk stratification before proximal aortic replacement.
doi:10.1016/j.jtcvs.2013.09.011
PMCID: PMC4336171  PMID: 24183336
24.  Metabolic and biochemical effects of low-to-moderate alcohol consumption 
Background
Alcohol consumption has multiple biochemical consequences. Only a few of these are useful as diagnostic markers but many reflect potentially harmful or beneficial effects of alcohol. Average consumption of two to four drinks per day is associated with lower overall or cardiovascular mortality risk than either lower or higher intake. We have analysed the dose-response relationships between reported alcohol consumption and 17 biomarkers, with emphasis on intake of up to three drinks per day.
Methods
Biochemical tests were performed on serum from 8396 study participants (3750 men and 4646 women, aged 51 ± 13 years, range 18–93) who had provided information on alcohol consumption in the week preceding blood collection.
Results
GGT, ALT, AST, CDT, urate, ferritin and bilirubin showed little or no change with alcohol consumption below two to three drinks per day, but increased with higher intake. HDL-C and albumin showed increasing results, and insulin showed decreasing results, across the entire range of alcohol use. Biphasic responses, where subjects reporting one to two drinks per day had lower results than those reporting either more or less alcohol use, occurred for triglycerides, glucose, C-reactive protein, alkaline phosphatase and butyrylcholinesterase. Increasing alcohol use was associated with decreasing LDL-C in younger women, but higher LDL-C in older men.
Conclusions
Some markers show threshold relationships with alcohol, others show continuous ones, and a third group show biphasic or U-shaped relationships. Overall the biochemical sequelae of low-to-moderate alcohol use are consistent with the epidemiological evidence on morbidity and mortality.
doi:10.1111/acer.12015
PMCID: PMC3568441  PMID: 23134229
Alcohol; Biomarkers; Dose-response curve; Population study
25.  Value of serum glycated albumin and high-sensitivity C-reactive protein levels in the prediction of presence of coronary artery disease in patients with type 2 diabetes 
Background
Coronary artery disease (CAD) is a major vascular complication of diabetes mellitus and reveals high mortality. Up to 30% of diabetic patients with myocardial ischemia remain asymptomatic and are associated with worse prognosis compared to non-diabetic counterpart, which warrants routine screening for CAD in diabetic population. The purpose of this study was to evaluate the clinical value of serum glycated albumin and high-sensitivity C-reactive protein (hs-CRP) levels in predicting the presence of CAD in patients with type 2 diabetes.
Methods
Three hundred and twenty-four patients with type 2 diabetes were divided into two groups based on presence (CAD group, n = 241) or absence (control group, n = 83) of angiographically-documented CAD (lumen diameter narrowing ≥70%). Serum levels of glycated albumin and hs-CRP as well as serum concentrations of glucose, lipids, creatinine, blood urea nitrogen and uric acid were measured in both groups. Predictors of CAD were determined using multivariate logistic regression model and receiver-operating characteristic (ROC) curves.
Results
Serum glycated albumin and hs-CRP levels were significantly increased in diabetic patients with CAD. Multivariate regression analysis revealed that male gender, age, serum levels of glycated albumin, hs-CRP, creatinine and lipoprotein (a) were independent predictors for CAD. Areas under the curve of glycated albumin and hs-CRP and for regression model were 0.654 (95%CI 0.579–0.730, P < 0.001), 0.721 (95%CI 0.658–0.785, P < 0.001) and 0.824 (95% CI 0.768–0.879, P < 0.001), respectively. The optimal values of cut-off point were 18.7% (sensitivity 67.9%, specificity 60.0%) for glycated albumin and 5.2 mg/l (sensitivity 72.2%, specificity 60.0%) for hs-CRP to predict CAD. Logistic regression model was defined as: P/(1-P) = EXP(-1.5 + 1.265 gender + 0.812 age + 1.24 glycated albumin + 0.953 hs-CRP + 0.902 lipoprotein(a) + 1.918 creatinine). The optimal probability value for predicting CAD in type 2 diabetic patients was 0.648 (sensitivity 82.3%, specificity 68.6%).
Conclusion
Serum glycated albumin and hs-CRP levels were significantly elevated in patients with type 2 diabetes and CAD. The logistic regression model incorporating with glycated albumin, hs-CRP and other major risk factors of atherosclerosis may be useful for screening CAD in patients with type 2 diabetes.
doi:10.1186/1475-2840-5-27
PMCID: PMC1764721  PMID: 17178005

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