Are Statistical Contributions to Medicine Undervalued?

Econometricians Daniel McFadden and James Heckman won the 2000 Nobel Prize in economics for their work on discrete choice models and selection bias. Statisticians and epidemiologists have made similar contributions to medicine with their work on case-control studies, analysis of incomplete data, and causal inference. In spite of repeated nominations of such eminent figures as Bradford Hill and Richard Doll, however, the Nobel Prize in physiology and medicine has never been awarded for work in biostatistics or epidemiology. (The "exception who proves the rule" is Ronald Ross, who, in 1902, won the second medical Nobel for his discovery that the mosquito was the vector for malaria. Ross then went on to develop the mathematics of epidemic theory--which he considered his most important scientific contribution-and applied his insights to malaria control programs.) The low esteem accorded epidemiology and biostatistics in some medical circles, and increasingly among the public, correlates highly with the contradictory results from observational studies that are displayed so prominently in the lay press. In spite of its demonstrated efficacy in saving lives, the "black box" approach of risk factor epidemiology is not well respected. To correct these unfortunate perceptions, statisticians would do well to follow more closely their own teachings: conduct larger, fewer studies designed to test specific hypotheses, follow strict protocols for study design and analysis, better integrate statistical findings with those from the laboratory, and exercise greater caution in promoting apparently positive results.     

Asymptotic Relative Risk Results from a Simplified Armitage and Doll Model of Carcinogenesis

We examine basic asymptotic properties of relative risk for two families of generalized Erlang processes (where each one is based off of a simplified Armitage and Doll multistage model) in order to predict relative risk data from cancer. The main theorems that we are able to prove are all corroborated by large clinical studies involving relative risk for former smokers and transplant recipients. We then show that at least some of these theorems do not extend to other Armitage and Doll multistage models. We conclude with suggestions for lifelong increased cancer screening for both former smoker and transplant recipient subpopulations of individuals and possible future directions of research.     

The effect of silica exposure on the risk of lung cancer: A meta-analysis

Lung cancer is an incurable disease with an increased mortality rate caused by the inhalation of dust-containing crystalline silica particles. Silica exposure is one of the most important occupational hazards in the world. Whether the association between silica exposure and lung cancer is because of the fibrotic process or to the effect of respirable silica itself is unclear. The International Agency for Research on Cancer (IARC) classified silica as a human lung carcinogen. The opinion of lung cancer is a question that has been addressed in this review. Three electronic databases, including MEDLINE, Scopus, and Web of Science, were used to search for relevant literature from 2000 to 2022. To evaluate the relationship between exposure to silica and developing lung cancer, we performed a meta-analysis using the random-effects model. For each study, the overall odds ratio (OR), relative risk (RR) with 95% confidence intervals (CI), and p values were calculated. An extensive database search resulted in the selection of 20 (case‒control and nested case‒control studies were selected) out of 527 studies. Among the 20 selected studies, 7 studies showed a significant association between silica exposure and an increased risk of lung cancer. Further analysis showed that among the selected studies, six studies showed a significant correlation between combined exposure to silica and smoking with an increased risk of lung cancer. The data from the present study showed that smoking habits increased the impact of silica exposure on the initiation of lung carcinogenesis in exposed workers.     

CCND1 G870A polymorphism interaction with cigarette smoking increases lung cancer risk: meta-analyses based on 5008 cases and 5214 controls

Evidence indicates CCND1 G870A polymorphisms as a risk factor for a number of cancers. Increasing studies have been conducted on the association of CCND1 G870A polymorphism with lung cancer risk. However, the results were controversial. The aim of the present study was to derive a more precise estimation of the relationship. Meta-analyses examining the association between CCND1 G870A polymorphism and lung cancer were performed. Subgroup analyses regarding ethnicity, smoking status, histological types and source of controls were also implemented. All eligible studies for the period up to May 2012 were identified. The overall data from ten case–control studies including 5,008 cases and 5,214 controls indicated that variant A allele may have an association with increased lung cancer risk (AA vs GG: OR = 1.21; 95 % CI = 1.08–1.36, dominant model: OR = 1.09; 95 % CI = 1.00–1.19, recessive model: OR = 1.23; 95 % CI = 1.01–1.49). In the subgroup analysis by ethnicity, A allele may elevate lung cancer risk among Asians but not Caucasians or Mixed ethnicities. In smoking status subgroup, A allele was shown to associate with increased lung cancer risk among smokers but not non-smokers. In the subgroup analysis by histological types, increased cancer risks were shown in adenocarcinoma but not squamous cell carcinoma, under the homozygote comparison and recessive models. Collectively, the results of the present study suggest that CCND1 G870A polymorphism might be a low-penetrant risk factor for lung cancer, particularly among Asians and smokers. Moreover, homozygous AA alleles might have a correlation with increased lung adenocarcinoma susceptibility.     

Does Exposure to Trichloroethene in Low Doses Constitute a Cancer Risk to Humans?

Although chronic exposure to high doses of trichloroethene causes tumors of the lung, liver, and kidney in experimental animals, the epidemiology data in humans exposed to trichloroethene as a whole fail to support a causal association between trichloroethene exposure and cancers of the lungs, liver, or kidneys in humans at environmentally relevant concentrations. Environmentally relevant concentrations of trichloroethene are defined as 50 ppb (50 µg/L) in water or 5 ppb (27 µg/m³) in air. Tumor induction by trichloroethene in rodents exposed to very high doses over their whole lifespan has been observed in the kidney of rats and in the lung and liver of mice. Mechanistic data demonstrate that species-specific processes are involved in the carcinogenicity associated with chronic trichloroethene exposure in rodents. Based on these data and the results of recent well-conducted epidemiology studies, it can be concluded that humans exposed to trichloroethene at environmentally relevant concentrations are not at an increased risk for developing cancer.     

Radial Scars and Subsequent Breast Cancer Risk: A Meta-Analysis

Background

The relationship between radial scars and breast cancer is unclear, as the results of different studies are inconsistent. We aim to solve the controversy and assess the breast cancer risk of radial scars.

Methods

Case-control or cohort studies about radial scars and breast cancer risk published in PubMed, Web of Science and the Cochrane Library from 2000 to 2013 were searched. Heterogeneity for the eligible data was assessed and a pooled odds ratio (OR) with 95% confidence interval (CI) was calculated.

Results

Five observational studies involving 2521 cases and 20290 controls were included in our study. From pooled analysis, radial scars were found to have a 1.33 fold increased risk of breast cancer, but which was not significant (P = 0.138). Sample size contributed to heterogeneity. In subgroup analysis, the results pooled from studies with sample size >2000 show that presence of radial scars was associated with 1.6 times breast cancer risk compared to absence of radial scars. Radial scars increased the risk of breast cancer among women with proliferative disease without atypia, but no significant association between radial scars and carcinoma was noted among women with atypical hyperplasia.

Conclusions

Radial scars tend to be associated with an increased breast cancer risk. Radial scars should be considered among women with proliferative disease without atypia, while atypical hyperplasia is still the primary concern among women with both radial scars and atypical hyperplasia.     

Chromosome 15q25 (CHRNA3-CHRNA5) variation impacts indirectly on lung cancer risk

Genetic variants at the 15q25 CHRNA5-CHRNA3 locus have been shown to influence lung cancer risk however there is controversy as to whether variants have a direct carcinogenic effect on lung cancer risk or impact indirectly through smoking behavior. We have performed a detailed analysis of the 15q25 risk variants rs12914385 and rs8042374 with smoking behavior and lung cancer risk in 4,343 lung cancer cases and 1,479 controls from the Genetic Lung Cancer Predisposition Study (GELCAPS). A strong association between rs12914385 and rs8042374, and lung cancer risk was shown, odds ratios (OR) were 1.44, (95% confidence interval (CI): 1.29–1.62, P = 3.69×10⁻¹⁰) and 1.35 (95% CI: 1.18–1.55, P = 9.99×10⁻⁶) respectively. Each copy of risk alleles at rs12914385 and rs8042374 was associated with increased cigarette consumption of 1.0 and 0.9 cigarettes per day (CPD) (P = 5.18×10⁻⁵ and P = 5.65×10⁻³). These genetically determined modest differences in smoking behavior can be shown to be sufficient to account for the 15q25 association with lung cancer risk. To further verify the indirect effect of 15q25 on the risk, we restricted our analysis of lung cancer risk to never-smokers and conducted a meta-analysis of previously published studies of lung cancer risk in never-smokers. Never-smoker studies published in English were ascertained from PubMed stipulating - lung cancer, risk, genome-wide association, candidate genes. Our study and five previously published studies provided data on 2,405 never-smoker lung cancer cases and 7,622 controls. In the pooled analysis no association has been found between the 15q25 variation and lung cancer risk (OR = 1.09, 95% CI: 0.94–1.28). This study affirms the 15q25 association with smoking and is consistent with an indirect link between genotype and lung cancer risk.     

XRCC1 gene polymorphisms and lung cancer susceptibility: a meta-analysis of 44 case–control studies

X-ray repair cross-complementing group 1 gene (XRCC1) has been implicated in risk for lung cancer. However, the results from different studies remain controversial. In this meta-analysis, we have assessed 44 published case-control studies regarding associations of lung cancer risk with three common polymorphisms, codon 194, codon 280 and codon 399, and -77 T?>?C in the promoter region of XRCC1. The results in total population showed that the risk for lung cancer was increased among the variant homozygote Trp/Trp of codon 194 polymorphism, compared with the wild type Arg/Arg (OR: 1.19; 95?% CI 1.01-1.39), and the variant genotype CC of -77 T?>?C polymorphism showed a significantly increased risk of developing lung cancer, compared to wild-type genotype TT (OR: 1.91; 95?% CI 1.24-2.94). However, no associations were found between lung cancer risk and codon 280, codon 399. In the subgroup analyses by ethnicity, the OR for the variant homozygote Trp/Trp of codon 194 was 1.21(95?% CI 1.02-1.43) for Asian. When stratified by source of control, we found a protective effect of codon 194 Arg/Trp genotype (OR: 0.87; 95?% CI 0.77-0.98) and risk effect of codon 399 combined Arg/Gln?+?Gln/Gln variant genotype (OR: 1.09; 95?% CI 1.01-1.18) for lung cancer on the basis of hospital control. Subgroup analyses by histological types of lung cancer indicated that the heterozygote Arg/Trp in codon 194 could decrease and the combined variant genotype Arg/Gln?+?Gln/Gln in codon 399 could increase the risk of non-small cell lung cancer (OR: 0.69; 95?% CI 0.57-0.85 and OR: 1.14; 95?% CI 1.04-1.24). In conclusion, this meta-analysis has demonstrated that codon 194, codon 399 and -77 T?>?C polymorphisms of XRCC1 gene might have contributed to individual susceptibility to lung cancer. To further evaluate effect of XRCC1 polymorphisms, gene-gene interaction and gene-environment interaction on lung cancer risk, a single large sample size study with thousands of subjects is required to get conclusive results.     

Richard Doll and Alice Stewart: reputation and the shaping of scientific "truth"

As the world watched the Fukushima reactors release radionuclides into the ocean and atmosphere, the warnings of Dr. Alice Stewart about radiation risk and the reassurances of Sir Richard Doll assumed renewed relevance. Doll and Stewart, pioneer cancer epidemiologists who made major contributions in the 1950s-he by demonstrating the link between lung cancer and smoking, she by discovering that fetal X-rays double the chance of a childhood cancer-were locked into opposition about low-dose radiation risk. When she went public with the discovery that radiation at a fraction of the dose "known" to be dangerous could kill a child, her reputation plummeted, whereas Doll, foremost among her detractors, was knighted and lauded as "the world's most distinguished medical epidemiologist" for his work. Their lives and careers, so closely intertwined, took contrary courses, he becoming "more of the establishment" (as he said), while she became more oppositional. When it was discovered, after his death, that he'd been taking large sums of money from industries whose chemicals he was clearing of cancer risk, his reputation remained unscathed; it is now enshrined in the "Authorized Biography" (2009) commissioned by the Wellcome Institute, along with Doll's denigration of Stewart as an "embittered" woman and biased scientist. Stewart lived long enough to see radiation science move her way, to see international committees affirm, in the 1990s, that there is no threshold beneath which radiation ceases to be dangerous; recent evidence from Chernobyl is bearing out her warnings. But a look at the making and breaking of these reputations reveals the power of status, position, and image to shape scientific "knowledge" and social policy.     

Glutathione S-transferase T1 gene deletion polymorphism and lung cancer risk in Chinese population: A meta-analysis

Genetic variations in metabolic genes are considered to modulate metabolic process of carcinogens and are suggested to be related to cancer risk. However, epidemiological results are not always consistent. In this meta-analysis, we evaluated reported studies of association between polymorphism of glutathione S-transferase T1 gene (GSTT1) and the risk of lung cancer in Chinese population. We found an increased lung cancer risk among subjects carrying GSTT1 null genotype [odds ratio (OR) = 1.36, 95 percent confidence interval (95% CI): 1.09–1.69], using 1625 cases and 2188 controls from 11 studies. We also observed an increased risk of lung cancer among null genotype carriers in squamous cell carcinoma and andenocarcinoma, and on the basis of population control in stratified analyses. The meta-analysis suggests that GSTT1 deletion polymorphisms may have an effect on the susceptibility of lung cancer in Chinese population, and a study with the larger sample size is needed to further evaluate gene–gene and gene–environment interaction on GSTT1 deletion polymorphisms and lung cancer risk in Chinese population.     

Mechanisms involved in lung cancer development in COPD

Lung cancer and chronic obstructive pulmonary disease (COPD) are leading causes of morbidity and mortality worldwide. They share a common environmental risk factor in cigarette smoke exposure and a genetic predisposition represented by the incidence of these diseases in only a fraction of smokers. COPD is also a major independent risk factor for lung carcinoma, among long-term smokers. Smokers with COPD also have a higher risk of developing a specific histological subtype of non-small cell lung cancer termed squamous cell carcinoma. For these reasons the focus of this review is on the potential pathogenic molecular links between tobacco smoking-related COPD and squamous cell carcinoma. We believe that we need to promote more studies on the molecular and cellular pathobiology of smokers with premalignant bronchial lesions of the squamous cell lung carcinoma compared with a control group of smokers with and without COPD to unravel the complex molecular interactions between COPD and early squamous cell lung carcinoma. These studies should also look at younger healthy smokers in combination with risk models of lung cancer and COPD. Overall these studies may allow the discovery of new molecular targets of the early carcinogenesis process that in the foreseeable future may render the early diagnosis and treatment, and may be even the prevention, of invasive squamous cell lung carcinoma a reality.     

C-reactive protein, interleukin 6 and lung cancer risk: a meta-analysis

Purpose

Epidemiologic findings are inconsistent concerning the associations between C-reactive protein (CRP), interleukin 6 (IL-6) and lung cancer risk. We conducted a meta-analysis of epidemiologic studies to examine these associations.

Methods

A systematic literature search up to October 2011 was performed in MEDLINE and EMBASE. Study-specific risk estimates were pooled using a random-effects model.

Results

The 10 studies on CRP involved a total of 1918 lung cancer cases. The pooled RR of lung cancer for one unit change in natural logarithm (ln) CRP was 1.28 (95% CI 1.17–1.41). There was no statistically significant heterogeneity among studies (P = 0.116; I² = 36.6%). We also found that CRP was significantly associated with increased risk of lung cancer among men (RR 1.18, 95% CI 1.09–1.28) but not among women. The 5 studies on IL-6 involved a total of 924 lung cancer cases. The pooled RR of lung cancer for one unit change in ln IL-6 was 1.28 (95% CI 0.92–1.79), however, statistically significant heterogeneity was found. After excluding the study contributing most to the heterogeneity, the summary estimate was essentially unchanged.

Conclusion

CRP was associated with increased risk of lung cancer, especially among men. There was no significant association between IL-6 and lung cancer risk.     

Methods for etiologic and early marker investigations in the PLCO trial

With the rapid development of biomarkers and new technologies, large-scale biologically-based cohort studies present expanding opportunities for population-based research on disease etiology and early detection markers. The prostate, lung, colorectal and ovarian cancer (PLCO) screening trial is a large randomized trial designed to determine if screening for these cancers leads to mortality reduction for these diseases. Within the Trial, the PLCO etiology and early marker study (EEMS) identifies risk factors for cancer and other diseases and evaluates biologic markers for the early detection of disease. EEMS includes 155,000 volunteers who provide basic risk factor information. Serial blood samples are collected at each of six screening rounds (including one collection for cryopreserved whole blood) from screening arm participants (77,000 subjects) and buccal cells are collected from those in the control arm of the trial. Etiologic studies consider environmental (e.g., diet), biochemical, and genetic factors. Early detection studies focus on blood-based biologic markers of early disease. Clinical epidemiology is also an important component of the PLCO trial.     

Methodologic challenges in chronic disease population research

Some recent important, and controversial, chronic disease population research settings are reviewed. These include studies of hormone replacement therapy and coronary heart disease; studies of dietary fat in relation to breast cancer; and studies of beta-carotene supplementation and lung cancer. In each case methodologic developments having a strong biostatistical component are identified as key to future progress. Some comments are also made on the need for an expanded disease prevention intervention development enterprise, and on the role that microarray genetic and genomic data may play in such development.     

Associations between Dietary Intake of Choline and Betaine and Lung Cancer Risk

Evidence from human and animal research indicates that choline metabolic pathways may be activated during a variety of diseases, including cancer. We report results of a case-control study of 2821 lung cancer cases and 2923 controls that assessed associations of choline and betaine dietary intakes with lung cancer. Using multivariable logistic regression analyses, we report a significant association between higher betaine intake and lower lung cancer risk that varied by smoking status. Specifically, no significant association was observed between betaine intake and lung cancer among never-smokers. However, higher betaine intake was significantly associated with reduced lung cancer risk among smokers, and the protective effect was more evident among current than former smokers: for former and current smokers, the ORs (95% CI) of lung cancer for individuals with highest as compared to lowest quartiles of intake were 0.70(0.55–0.88) and 0.51(0.39–0.66) respectively. Significant linear trend of higher betaine intake and lower lung cancer risk was observed among both former (p_trend = 0.002) and current (p_trend<0.0001) smokers. A similar protective effect was also observed with choline intake both in overall analysis as well as among current smokers, with p-values for chi-square tests being 0.001 and 0.004 respectively, but the effect was less evident, as no linear trend was observed. Our results suggest that choline and betaine intake, especially higher betaine intake, may be protective against lung cancer through mitigating the adverse effect of smoking.     

Smoking,Chronic Bronchitis,and Lung Cancer

A follow-up was carried out on 21,579 male mass radiography volunteers aged at least 40 who had been the subject of an earlier investigation in which their smoking habits and sputum production were recorded and the prevalence of lung cancer was determined after chest x-ray examination. During the follow-up period, which was a minimum of 36 months and a maximum of 56 months, 64 new cases of lung cancer were identified by cross checking records with the registers of the regional cancer registration bureau. A significantly higher incidence of lung cancer was found in those with chronic bronchitis than in those without this disease. In the smoking categories, cigarette smokers with chronic bronchitis had a higher incidence than those without it, and this relationship was maintained irrespective of age and amount smoked. It is concluded that persons who smoke run a higher risk of chronic bronchitis than non-smokers and those who develop bronchitis run a higher risk of developing lung cancer.     

Mortality in relation to smoking: 22 years' observations on female British doctors.

A total of 6194 female doctors who in 1951 replied to a questionnaire about their smoking habits were followed up prospectively for 22 years. During that time 1094 died. Ischaemic heart disease, lung cancer, and chronic obstructive lung disease were all significantly (p < 0.001) related to smoking, though the absolute excess risks were lower than in male doctors smoking equivalent amounts. Female smokers born before the first world war were less likely to describe themselves as inhalers or as having started to smoke while young than were female smokers who were born later. In these respects this younger group resembled male smokers, and as they move into their 60s and 70s their absolute risk of lung disease and relative risk of ischaemic heart disease will probably come to resemble the risks for men smoking the same numbers of cigarettes. These findings show only that cigarette smoking causes lung cancer, chronic obstructive lung disease, and heart disease in women as in men. Whether the proportional increase in mortality from these diseases is as great in women as in men might be estimated directly from new case-control studies on men and women born since 1920.     

Association between Chronic Obstructive Pulmonary Disease and Lung Cancer: A Case-Control Study in Southern Chinese and a Meta-Analysis

Background

Lung cancer and chronic obstructive pulmonary disease (COPD) share a common risk factor in cigarette smoking and a large portion of patients with lung cancer suffer from COPD synchronously. We therefore hypothesized that COPD is an independent risk factor for lung cancer. Our aim was to investigate the intrinsic linkage of COPD (or emphysema, chronic bronchitis and asthma) and lung cancer.

Methods

The present hospital-based case-control study included 1,069 patients with newly diagnosed lung cancer and 1,132 age frequency matched cancer-free controls. The odds ratios (ORs) for the associations between each previous pulmonary disease and lung cancer were estimated with logistic regression models, adjusting for age, sex, family history of cancer, BMI and pack year smoking. In meta-analysis, the pooled effects of previous pulmonary diseases were analyzed with random effects models; and stratification analyses were conducted on smoking status and ethnicity.

Results

In the case-control study, previous COPD was associated with the odds for increased risk of lung cancer (OR = 1.29, 95% confidence interval [CI] = 1.00∼1.68); so were emphysema (OR = 1.55, 95%CI = 1.03∼2.32) and chronic bronchitis (OR = 1.22, 95%CI = 0.99∼1.67); while asthma was associated with odds for decreased risk of lung cancer (OR = 0.29, 95%CI = 0.16∼0.53). These associations were more pronounced in smokers (P<.05 for all strata), but not in non-smokers. In meta-analysis, 35 studies (22,010 cases and 44,438 controls) were identified. COPD was significantly associated with the odds for increased risk of lung cancer (pooled OR = 2.76; 95% CI = 1.85–4.11), so were emphysema (OR = 3.02; 95% CI = 2.41–3.79) and chronic bronchitis (OR = 1.88; 95% CI = 1.49–2.36); and these associations were more pronounced in smokers than in non-smokers (P<.001 respectively). No significant association was observed for asthma.

Conclusion

Previous COPD could increase the risk of lung cancer, especially in smokers.     

Chronic Obstructive Pulmonary Disease and Altered Risk of Lung Cancer in a Population-Based Case-Control Study

Background

Chronic obstructive pulmonary disease (COPD) has been consistently associated with increased risk of lung cancer. However, previous studies have had limited ability to determine whether the association is due to smoking.

Methodology/Principal Findings

The Environment And Genetics in Lung cancer Etiology (EAGLE) population-based case-control study recruited 2100 cases and 2120 controls, of whom 1934 cases and 2108 controls reported about diagnosis of chronic bronchitis, emphysema, COPD (chronic bronchitis and/or emphysema), or asthma more than 1 year before enrollment. We estimated odds ratios (OR) and 95% confidence intervals (CI) using logistic regression. After adjustment for smoking, other previous lung diseases, and study design variables, lung cancer risk was elevated among individuals with a history of chronic bronchitis (OR = 2.0, 95% CI = 1.5–2.5), emphysema (OR = 1.9, 95% CI = 1.4–2.8), or COPD (OR = 2.5, 95% CI = 2.0–3.1). Among current smokers, association between chronic bronchitis and lung cancer was strongest among lighter smokers. Asthma was associated with a decreased risk of lung cancer in males (OR = 0.48, 95% CI = 0.30–0.78).

Conclusions/Significance

These results suggest that the associations of personal history of chronic bronchitis, emphysema, and COPD with increased risk of lung cancer are not entirely due to smoking. Inflammatory processes may both contribute to COPD and be important for lung carcinogenesis.     

Urinary excretion of 8-oxo-7,8-dihydroguanine as biomarker of oxidative damage to DNA

Oxidatively damaged DNA may be important in carcinogenesis. 8-Oxo-7,8-dihydroguanine (8-oxoGua) is an abundant and mutagenic lesion excised by oxoguanine DNA glycosylase 1 (OGG1) and measurable in urine or plasma by chromatographic methods with electrochemical or mass spectrometric detectors, reflecting the rate of damage in steady state. A common genetic OGG1 variant may affect the activity and was associated with increased levels of oxidized purines in leukocytes without apparent effect on 8-oxoGua excretion or major change in cancer risk. 8-OxoGua excretion has been associated with exposure to air pollution, toxic metals, tobacco smoke and low plasma antioxidant levels, whereas fruit and vegetable intake or dietary interventions showed no association. In rodent studies some types of feed may be source of 8-oxoGua in collected urine. Of cancer therapies, cisplatin increased 8-oxoGua excretion, whereas radiotherapy only showed such effects in experimental animals. Case-control studies found high excretion of 8-oxoGua in relation to cancer, dementia and celiac disease but not hemochromatosis, although associations could be a consequence rather than reflecting causality of disease. One prospective study found increased risk of developing lung cancer among non-smokers associated with high excretion of 8-oxoGua. Urinary excretion of 8-oxoGua is a promising biomarker of oxidatively damaged DNA.