Application Of Meta-analysis And Biostatistical Models For The Risk Assessment Of Population Health Hazard Exposed To PAHs

Polycyclic aromatic hydrocarbons (PAHs) are an important kind of environmentalchemical pollutants (ECPs) which had been reported to have health-hazard ability evento cause DNA damage and lead to carcinogenesis.But at present, we can not absolutelyprohibit PAHs emission, PAHs pollutants will not become extinct soon and evencontinually exist for a long time.How to correctly assess their risks might be anessential and valuable exercise.In this research, we carried out a Meta-analysis to appraise the relevant publishedresearches and used several biostatistical models and methods such as the artificialneural network (ANN) model, the multifactor dimensionality reduction (MDR), toanalyze a cross-sectional research in coke-oven workers in a northern steel plant, and acase-control study of a hospital-community based population in South China.Risk ofhealth hazard in Chinese occupational and ordinary population who exposed to PAHspollutants, and the values of Meta-analysis and biostatistical models in the riskassessments were explored and discussed.Part one: Meta-analysis method and its application in PANs risk assessmentObjectives (1)To explore the role and application of Meta-regression andsubgroup analyses to recognize and control the heterogeneity; (2) To explore how tocorrectly choose and judge Egger's test and Begg's test to detect the publication bias inMeta-analysis; and (3) Genetic polymorphisms of cytochrome p4501A1 (CYP1A1) andglutathione S-transferase M1 (GSTM1) genes are thought to have significant effects on the metabolism of environmental carcinogens, but the reported results are not alwaysconsistent.We tried to find evidences of an association between the CYP1A1 variant andGSTM1 null genotypes and increased risk of lung cancer in Chinese populations.Methods 1.Meta-regression models were established using database 1 from casecontrolstudies of lung cancer in passive smoking females to search for theheterogeneous factors, and the change of heterogeneity were compared before and aftersubgroup analyses.2.Database 2 included 28 papers about Interleukin polymorphismsand gastric cancer risk, and 11 pieces of random or tendency missing datasets wereobtained.Egger's test, Begg's test and funnel plot et al.were used to diagnose thepublication bias then the differences were compared.Heterogeneity and normaldistribution tests were also offered.3.Through a systematic literature search forpublications between 1989 and 2008, we summarized the data from 54 studies onpolymorphisms of MspI and Exon7 of CYP1A1 and GSTM1 and lung cancer risk inChinese populations.Our results also were compared with other ethic populations.Results 1.The heterogeneity of the database 1 was existed in the Meta-analysis(Q=44.71, P=0.017).Sample size and region were selected (P=0.012 and P=0.091,respectively) by Meta-regression.The Q values were lowered after subgroup analyses.2.For the database 2, (1) Among random missing, the results of Egger's test andBegg's test are all greater than 0.05; while missing with tendency, P-values of Egger'stest are all greater than 0.05 while Begg's test are less than 0.05 and funnel plotsappeared to be asymmetrical which suggested a potential publication bias; and (2) Theheterogeneity and normal tests are almost significant in missing with tendency.3.(1) Compared with the type A, lung cancer risk for the types B and C was 1.35-fold (95% confidence interval [CI]=1.11-1.65) (Z=3.01, P=0.003); (2) The risk forthe Ile/Val and Val/Val of CYP1A1 Exon7 was 1.55-fold (95% CI=1.22-1.97) (Z=3.61, P<0.001), compared with the Ile/Ile genotype; and (3) The risk for the GSTM1null genotype was 1.63-fold (95% CI=1.40-1.88) (Z=6.51, P<0.001), comparedwith the present genotype.(4) Compared with the other ethnic, we found thesusceptivity to lung cancer in Caucasian was not obviously increased or increasedmuch less than the Chinese populations. Conclusions 1.Meta-regression method is convenient and reliable to search forthe affected factors of heterogeneity, and subgroup analyses based on that cansignificantly lower the heterogeneity.2.Missing with tendency can lead to publicationbias while random missing not.In missing of tendency, Begg's test is easier todiagnose the publication bias than Egger's test.Abnormal distribution of the samplesize and significant heterogeneity are the possible influencing factors of the power ofEgger's test.3.We found evidence of an association between the CYP1A1 variant andGSTM1 null genotypes and increased risk of lung cancer in Chinese populations.Moreover, there is a significant ethnic difference in CYP1A1, GSTM1 polymorphismsand the lung cancer risk.Part Two: Application of biostatistical models in PAHs risk assessmentsObjective Populations who exposed to PAHs pollutant can cause health damageand lead to carcinogenesis.Therefore, it is critical to identify biomarkers that predictearly health damage in these exposed individuals in molecular epidemiological studies.It is also valuable to explore the dose-response relationship and gene-gene-environmentinteraction effects in the risk assessment in the PAHs exposure.Methods The database 1 included 330 steel-factory workers who were exposedto different levels of PAHs in the workplace and their levels of early health damagewere determined by micronuclei (MN) rate, heat shock protein 70 (Hsp70) level,benzo(α) pyrene diolepoxide-albumin adduct (BPDE-AA), and Olive tail moment(Olive TM).The ANN model was simulated to predict the health damage index, andthe receiver operating characteristic (ROC) curve was used to illustrate the judgmentcriteria and the ANN model.Multiple correspondence analysis (MCA) and trend Chisquarewere also offered to analyze the possible dose-response relationship betweenworkplace, service years and the degree of early health damage in these coke-ovenworkers.The database 2 of 16 genes and 65 SNPs (single nucleotide polymorphism, SNP)positions which were possibly affected the PAHs metabolism were collected from acase-control study including 500 lung cancer patients and 517 controls, as well as the 6 main environmental factors.After the tests of the Hardy-Weinberg equilibrium, thegene-gene interactions as well as the gene-environment interactions models weresimulated by the MDR software, and logistic regression was carried out to furtherobserve the form and the effect size of the interaction as a supplement to MDR.Results Coke-oven workers data: (1) There were 55 subjects with early healthdamage among 330 workers based on the multi-biomarker criteria using the 95percentile as the cut-off value, while there were 22-35 positive subjects if screening byany single biomarker.(2) Six variables which could be easily detected such asworkplace, cholesterol, were selected to simulate the ANN model.The area underROC (AUROC) was 0.726±0.037 (P<0.001).(3) Corresponding relationship andrelevance were existed among the exposure of workplace, service years and the degreeof early health damage in coke-oven workers.Moreover, the trend test was statisticallysignificant (Z=3.24, P=0.001).Case-control study data: (1) The test of Hardy-Weinberg equilibrium to all SNPs inthe control group suggested that it is a Hardy-Weinberg equilibrium population (P=0.24-0.97); (2) With the heterozygous polymorphism of rs4646782 position of thealdehyde dehydrogenase 2 (ALDH2) gene and rs2158041 position of aryl hydrocarbonacceptor (AhR) gene, as well as "long years of smoking" combinations were judged as"high-risk" population, else other combinations were discriminated as the "low-risk"population.The risk of lung cancer in "high-risk" population was 2.637 times (OR=2.637, 95% CI=2.047-3.403) as compared with the "low-risk" combinations.(3) Thecombination of"rs4646782 ~* rs2158041" gene polymorphisms had the multiplicationeffect, and "rs4646782 + rs2158041 + smoking year" has the additive effect; the productor the additive of the interaction terms increased a lung cancer risk of 0.097 or 0.199times as a value of product term was changed, respectively.Conclusions 1.(1) MN frequency, Hsp70, BPDE-AA level, and Olive TM couldbe used collectively to do a screening test of early health damage in coke-oven workers.Moreover, the effect of using multi-biomarker was much superior to any singlebiomarker.(2) The ANN model could be used to predict the degree of early healthdamage, and its performance was identified by AUROC which suggested that the determination the effect of multi-biomarker and the cut-off criterion were correctly.(3)MCA can visually reveal the relationships between PAHs exposure and effect; therefore,MCA can be applied as an auxiliary method to determine whether there is a doseresponserelationship in a research.2.The three factors including rs4646782, rs2158041 polymorphisms and smokingyear have the remarkable interaction of the lung cancer risk in the southern Chinesepopulation, and the combination of"high-risk" may increase 1.637 times of lung cancerrisk compared with "low-risk'.Moreover, our findings suggest that using the MDRmethod to analyze the multi-factor disease in the gene-gene and gene-environmentinteraction is practical and feasible and has a wide and good application prospect.Thelogistic regression may be used as a supplied method after MDR to analyze the formsand the effect size of interaction.In summary, in our study, the early health damage as well as some environmentalfactor and the hereditary factors (gene polymorphisms and race and ethnic difference)to the population-based healthy risk influence after the human body exposed to PAHswas discussed.We initially established risk evaluated system and the methods ofenvironment pollutant to the health hazard in Chinese populations based on Metaanalysis,the multi-biomarker, ANN, MCA, and MDR models.Our findings also can provide the biostatistical methods and the applicationpattern in the further researches on early health damage even lung cancer and of themacro- and micro- scope risk and damage mechanism exposed to PAHs.The results ofour research might offer a methodology foundation to establish the early precautionsystem of PAHs and even other ECPs.