Baseline micronuclei frequency in children: estimates from meta- and pooled analyses.The number of studies evaluating the effect of environmental exposure to genotoxic genotoxic /ge·no·tox·ic/ (je´no-tok?sik) damaging to DNA: pertaining to agents known to damage DNA, thereby causing mutations, which can result in cancer. ge·no·tox·ic adj. agents in children has rapidly increased in the last few years. The frequency of micronuclei (MN) in peripheral blood lymphocytes Peripheral Blood Lymphocytes (PBL): These are the mature lymphocytes (small white immune cells) that are found circulating in the blood, as opposed to organs, such as the lymph nodes, spleen, thymus, liver or bone marrow. These cells consist of T cells, NK cells and B cells. determined with the cytokinesis cytokinesis: see mitosis. Cytokinesis The physical partitioning of a plant or animal cell into two daughter cells during cell reproduction. block assay is among the most popular biomarkers used for this purpose, although large inter- and intralaboratory variability of this end point has been observed in population studies. The availability of reference measures is therefore necessary for laboratories to validate protocols and analytical procedures Analytical Procedures is one of financial audit skill which help an auditor understand the client's business and changes in the business, to identify potential risk areas and to plan other audit procedures. , and for molecular epidemiologists, as well, to estimate the statistical power of studies and to assess the quality of data. In this article, we provide estimates of the baseline frequency of MN in children, conducting a meta-analysis of MN frequency reported by field studies in children and a pooled analysis of individual data (available from published studies and from the Human Micronucleus micronucleus /mi·cro·nu·cle·us/ (-noo´kle-us) 1. in ciliate protozoa, the smaller of two types of nucleus in each cell, which functions in sexual reproduction; cf. macronucleus. 2. a small nucleus. International Collaborative Study (HUMN) database]. Thirteen articles were selected for meta-analysis, and individual data included in the pooled analysis were retrieved from the databases of 12 laboratories. Overall means of 4.48 [95% confidence interval confidence interval, n a statistical device used to determine the range within which an acceptable datum would fall. Confidence intervals are usually expressed in percentages, typically 95% or 99%. (CI), 3.35-5.98] and 5.70 (95% CI, 4.29-7.56) MN per 1,000 binucleated bi·nu·cle·ate also bi·nu·cle·at·ed or bi·nu·cle·ar adj. Having two nuclei. Adj. 1. binucleated - having two nuclei binuclear, binucleate cells were estimated by the meta- and pooled analysis, respectively. A clear effect of age was detected, even within the restricted range of pediatric pediatric /pe·di·at·ric/ (pe?de-at´rik) pertaining to the health of children. pe·di·at·ric adj. Of or relating to pediatrics. age considered, with significantly lower frequency values in newborns. No influence of sex was found. The study showed the advantage of using data from large collaborative studies and suggested a synergistic synergistic /syn·er·gis·tic/ (sin?er-jis´tik) 1. acting together. 2. enhancing the effect of another force or agent. syn·er·gis·tic adj. 1. use of meta- and pooled analysis. Key words: biomarker biomarker /bio·mark·er/ (bi´o-mahr?ker) 1. a biological molecule used as a marker for a substance or process of interest. 2. tumor marker. bi·o·mark·er n. 1. , children, environmental exposure, genetic damage, meta-analysis, micronucleus assay, molecular epidemiology molecular epidemiology Molecular medicine An evolving field that combines the tools of standard epidemiology–case studies, questionnaires and monitoring of exposure to external factors with the tools of molecular biology–eg, restriction endonucleases, , pooled analysis. doi:10.1289/ehp.7806 available via http://dx.doi.org/[Online 31 May 2005] ********** The number of studies evaluating the effect of environmental exposure to genotoxic agents in children has rapidly grown in the last years (Neri et al. 2005b; Suk SUK Sveriges Unga Katoliker (Swedens Young Catholics) et al. 2003), boosted by two main considerations: a) Children may be more sensitive than adults to genotoxic agents, and b) genetic damage occurring at young ages may affect the lifetime risk of delayed adverse health outcomes (Landrigan et al. 2003; Wild and Kleinjans 2003). Among the several adverse health effects that have been studied in children exposed to environmental hazards 'Environmental hazard' is a generic term for any situation or state of events which poses a threat to the surrounding environment. This term incorporates topics like pollution and Natural Hazards such as storms and earthquakes. , genetic damage has received a particular interest, especially after the recent publication of epidemiologic studies epidemiologic study A study that compares 2 groups of people who are alike except for one factor, such as exposure to a chemical or the presence of a health effect; the investigators try to determine if any factor is associated with the health effect showing that a high frequency of chromosome damage predicts cancer in healthy adults (Bonassi et al. 2004). The use of genetic biomarkers in children raises a number of issues (Neri et al. 2005a). On the other hand, studies in children are essential to make use of the findings in public and environmental health. Ethical issues are related to protection of privacy, causing no harm, and leaving the child with a "feel-good experience." Legal issues of data protection, confidentiality, and autonomy of the child are also important. Further, a direct application to pediatric populations of biomarkers of genetic damage that have been proven useful in adults may be misleading. Differences in exposure to and intake of environmental agents, xenobiotic xen·o·bi·ot·ic adj. Foreign to the body or to living organisms. Used of chemical compounds. n. A xenobiotic chemical. xenobiotic any substance, harmful or not, that is foreign to the animal's biological system. metabolism, and the role of infectious diseases infectious diseases: see communicable diseases. may alter the reliability of some biomarkers when translated from adults to children. Finally, to allow a correct interpretation of findings from these studies, a basic question must be addressed: What is the estimate of the spontaneous occurrence of genetic damage in children? The micronucleus (MN) test in peripheral blood lymphocytes with the cytokinesis block method is one of the most popular assays of genetic damage in human biomonitoring (Bonassi et al. 2005). Details about the assay can be found in the articles published by the Human Micronucleus International Collaborative Study (HUMN) (Fenech et al. 1999, 2003). The growing interest in this test, mostly due to the easy use of MN in monitoring exposure to genotoxic agents, is fueled also by the accumulating evidence that the frequency of MN in healthy subjects may be considered a marker of risk for cancer (Tucker and Preston 1996) and cardiovascular disease Cardiovascular disease Disease that affects the heart and blood vessels. Mentioned in: Lipoproteins Test cardiovascular disease (Andreassi and Botto 2003). The performance of this biomarker in field studies involving children exposed to environmental agents has been recently reviewed (Neri et al. 2003, 2005b). Despite the large number of advantages that justify the popularity of this assay, there is an evident limitation--the large inter- and intralaboratory variability in the MN frequency. This variability may be explained partially by technical reasons, genetic variability Introduction Genetic Variability
The meta- and pooled analyses represent the ideal statistical tools for computing summary estimates of a biomarker frequency using data from different studies (Greenland 1987). The advantages and the limitations of meta- and pooled analysis have been discussed in many articles, and in many aspects these methods are complementary (Taioli and Bonassi 2002). In this study, we identified the published studies reporting MN during childhood (age range, 0-18 years) with the aim of performing a meta-analysis of MN frequency for referent ref·er·ent n. A person or thing to which a linguistic expression refers. Noun 1. referent - something referred to; the object of a reference children and providing a meta-estimate of the MN baseline value. Moreover, a pooled analysis of individual data available from published studies and from the HUMN database (Bonassi et al. 2001) was performed with the same purpose. Materials and Methods Search strategy and studies selection. Individuals from birth to late adolescence (age range, 0-18 years) were considered as children. The studies selected for inclusion in the meta-analysis were identified by systematically searching the MedLine/PubMed database (National Library of Medicine, National Institutes of Health, Bethesda, MD, USA; http://www.ncbi.nlm.nih.gov/PubMed). The terms "micronucleus tests A micronucleus test is a test used in toxicological screening for potential genotoxic compounds. In vitro culture cells are checked for induced micronucleus formation. A micronucleus is the erratic (third) nucleus that is formed during the anaphase of mitosis. " existing since 1989 and "micronuclei" existing since 1990 were used as medical subject heading (MESH) key word. To cover previous years, a free text search with terms "micronucleus" and "micronuclei" was performed. The categories "All Child: 0-18 years," "Human," "Language: English," and "Publication Date: from January 1st, 1985 to September 1st, 2004" were set as search limits. This allowed retrieving 168 citations. Only studies measuring MN frequency in lymphocytes Lymphocytes Small white blood cells that bear the major responsibility for carrying out the activities of the immune system; they number about 1 trillion. with the cytokinesis block method (Fenech and Morley 1985) and with at least 10 subjects in the referent group were included. Referent children exposed to genotoxic agents or affected by any disease were also excluded from the statistical analyses. MN frequency was always reported as the number of MN per 1,000 (%o) binucleated cells. According to according to prep. 1. As stated or indicated by; on the authority of: according to historians. 2. In keeping with: according to instructions. 3. these criteria, 13 studies (Table 1), accounting for 440 subjects, were found to be suitable for the meta-analysis (Barale et al. 1998; Bilban and Vaupotic 2001; Da Cruz et al. 1994; Dulout et al. 1996; Fellay-Reynier et al. 2000; Fenech et al. 1997; Livingston et al. 1997; Maluf and Erdtmann 2001; Migliore et al. 1991; Mikhalevich et al. 2000; Shi et al. 2000; Vleminckx et al. 1997; Zotti-Martelli et al. 1999). One study with a small number of 19-year-old subjects was also included (Barale et al. 1998). Three different referent groups identified in a single study (Vleminckx et al. 1997) were treated as independent in the analysis. Six of the 13 studies included in the meta-analysis reported individual data for 103 children (da Cruz et al. 1994; Dulout et al. 1996; Fellay-Reynier et al. 2000; Maluf and Erdtmann 2001; Migliore et al. 1991; Mikhalevich et al. 2000) and were used also in the pooled analysis, together with 229 subjects from the HUMN database (Bonassi et al. 2001). Statistical methods. Meta-analysis. We computed a summary estimate of the MN frequency applying the random-effects linear model to the natural logarithm Natural logarithm Logarithm to the base e (approximately 2.7183). of the MN mean of each study (DerSimonian and Laird 1986). This model takes into account two sources of variability: the error in estimating the ith MN mean in repeated samples from the same population the ith study belongs to, and the heterogeneity het·er·o·ge·ne·i·ty n. The quality or state of being heterogeneous. heterogeneity the state of being heterogeneous. between studies. Although the former variability is assumed to be known and estimated by the standard error reported for each study, the latter (heterogeneity) was estimated from the model and found to be highly significant [Q = 308.14 (14 df), p < 0.001]. The analysis was carried out with STATA statistical software (STATA statistical software, release 7.0; Stata Corp., College Station, TX, USA); the random-effects model was performed with the procedure META, and the diagnostics, such as funnel plot, with the procedures METAINF and METABIAS. Pooled analysis. We obtained sex-specific and age-group-specific MN mean frequencies by fitting a negative binomial binomial (bī'nō`mēəl), polynomial expression (see polynomial) containing two terms, for example, x+y. The binomial theorem, or binomial formula, gives the expansion of the nth power of a binomial (x+ random-effects model to the MN count of each subject (Lindsey 1995). The negative binomial model was used to account for data overdispersion, whereas the clustered nature of data (i.e., the fact that the correlation between data within laboratories is likely to be larger than that between laboratories) was taken into consideration by introducing in the model a random effect due to the laboratory. The analysis was performed with MLwiN statistical software (version 1.10; Centre for Multilevel mul·ti·lev·el adj. Having several levels: a multilevel parking garage. Adj. 1. multilevel - of a building having more than one level Modelling, Institute of Education, University of London For most practical purposes, ranging from admission of students to negotiating funding from the government, the 19 constituent colleges are treated as individual universities. Within the university federation they are known as Recognised Bodies , London, UK). Results Meta-analysis. The MN frequency for each study included in the meta-analysis is reported in Table 1 along with the size of the study and the age range investigated. The overall meta-estimate of the MN frequency was 4.48 %o [95% confidence interval (CI), 3.35-5.98]. To evaluate the impact of single studies on this summary estimate of MN frequency, we performed a sensitivity analysis estimating the overall MN frequency after cyclically removing single studies. This approach showed the absence of influential studies, with meta-estimates of the MN frequency ranging from 4.77 to 4.22 %o. Pooled analysis. The layout of data selected for the pooled analysis is reported in Table 2. This analysis is more powerful with respect to meta-analysis because potential confounding confounding when the effects of two, or more, processes on results cannot be separated, the results are said to be confounded, a cause of bias in disease studies. confounding factor factors, such as age and sex, are accounted for. Age-group-specific and sex-specific pooled estimates computed from the random-effects model are shown in Table 3. Poor information was available about ethnic characteristics, although the large majority of children in the study came from European countries. The pooled mean estimate of the MN frequency was 5.70 %o (95% CI, 4.29-7.56) when all 332 referent subjects were considered. While pooled-mean values were similar for males (5.94 %o; 95% CI, 4.39-8.04) and females (5.54 %o; 95% CI, 4.13-7.4), MN frequency was clearly associated with age. Frequency values were very low in children < 1 year of age (3.27 %o; 95% CI, 2.22-4.82) and increased significantly thereafter, reaching the level of 7.05 %o (95% CI, 5.01-9.94) in the 15- to 19-year-old age group (chi-square test chi-square test: see statistics. for trend, p < 0.001). Discussion The main purpose of this study was to provide reference values ref·er·ence values pl.n. A set of laboratory test values obtained from an individual or from a group in a defined state of health. for researchers planning studies on genomic damage in children. We used two complementary approaches to compute summary measures of baseline MN frequency in children. Meta-analysis provided summary measures that, although affected by a certain degree of heterogeneity, are considered to be representative of studies published in the literature. Pooled analysis, although limited to six published studies (those for which individual data were available), included 229 subjects (from six laboratories) from the HUMN database (Bonassi et al. 2001) and allowed the computation of pooled estimates adjusted for age and sex. The estimates of the baseline MN frequency in children obtained by the two approaches were by large consistent, especially considering CIs. The lower mean value estimated by meta-analysis (4.48 vs. 5.70 %o, adjusted for age and sex), considering that mean ages in the laboratories contributing data to meta-analysis and in those considered for the pooled analysis were similar, is likely to be attributable to a different distribution of absolute values of MN frequency in the two sets of data. This is not surprising because studies based on cytogenetic cytogenetic /cy·to·ge·net·ic/ (-je-net´ik) 1. pertaining to chromosomes. 2. pertaining to cytogenetics. cytogenetic pertaining to or originating from the origin and development of the cell. biomarkers suffer from a certain degree of heterogeneity among laboratories, and absolute values may differ even largely. The availability of reference values is important for research teams and laboratories that need to validate protocols and analytical procedures as well as to estimate the statistical power of field studies and check the quality of data. For this purpose, baseline MN frequencies for the cytokinesis block assay have been published for an adult population (Bonassi et al. 2001). Age is the most important predictor of MN frequency, as described by cooperative studies and reported in the literature (Bolognesi et al. 1997; Bonassi et al. 2001). However, despite the high number of subjects evaluated, only differences between the extent of genetic stability in adults and in children were described. Recently, data from a review of studies conducted in children exposed to a variety of mutagens, although limited, pointed to an influence of age even in the first two decades of life (Ned et al. 2003). In the present study, the effect of age was evident even within the restricted age range considered in pooled analysis (0-19 years). The low frequency of MN detected in children < 1 year of age is noteworthy, given the growing number of studies performed on the cord blood cord blood n. Blood present in the umbilical vessels at the time of delivery. , an easily accessible source of DNA DNA: see nucleic acid. DNA or deoxyribonucleic acid One of two types of nucleic acid (the other is RNA); a complex organic compound found in all living cells and many viruses. It is the chemical substance of genes. . MN numbers were very low at birth (3.27 %0) and increased by 66% in children 1-4 years of age (5.43 %o), an increase that accounted for most of the age effect on MN frequency described in the literature. Besides the major challenges posed by the leaving of the protected intrauterine intrauterine /in·tra·uter·ine/ (-u´ter-in) within the uterus. in·tra·u·ter·ine adj. Within the uterus. Intrauterine Situated or occuring in the uterus. environment, other changes occurring in the first years of age, such as solid diet, vaccinations, and viral diseases viral diseases Diseases caused by viruses. Long-term immunity usually follows viral childhood diseases (see chickenpox). The common cold recurs into adulthood because many different viruses cause its symptoms, and immunity against one does not protect against others. , provide plausible explanations for this dramatic increase. No difference in MN frequency was found by sex in our pooled analysis. The effect of sex has been repeatedly reported in adult populations, and a recently published pooled analysis estimated a 19% higher MN frequency in females than in males (Bonassi et al. 1995, 2001). However, the influence of sex was limited (and not statistically significant) in subjects [less than or equal to] 40 years of age and became more pronounced in older subjects (Bonassi et al. 2001). Possible biologic explanation include a sex-related aneuploidy aneuploidy /an·eu·ploi·dy/ (an?u-ploi´de) any deviation from an exact multiple of the haploid number of chromosomes, whether fewer or more. an·eu·ploi·dy n. phenomenon and the implication of sexual hormones (Bonassi et al. 1995). Findings reported by Neri et al. (2003) failed to show any clear effect of sex on MN frequency, in children. In conclusion, these results address an increasing request from researchers performing epidemiologic studies in children based on biomarkers--specifically, the availability of specific reference values in pediatric populations. The MN baseline values provided here are meant for the planning phase In amphibious operations, the phase normally denoted by the period extending from the issuance of the order initiating the amphibious operation up to the embarkation phase. The planning phase may occur during movement or at any other time upon receipt of a new mission or change in the of a study and should not justify the conduct of future studies among children that exclude the identification of properly selected referent (control) subjects. Besides the main study findings, we showed here the advantage of using data from large collaborative research projects to improve the design of future field studies, including the efficiency of the statistical analysis. We thank M. Kitsch-Volders, Brussels, Belgium, for useful discussion. The study was supported by grants funded by the Associazione Italiana per la Ricerca sul Cancro and the European Union European Union (EU), name given since the ratification (Nov., 1993) of the Treaty of European Union, or Maastricht Treaty, to the European Community Fifth Framework Programme (QLK4-CT-2000-00628, QLK4-CT-2002-02831, and QLK4-CT-2002-02198). The authors declare they have no competing financial interests. Received 30 November 2004; accepted 31 May 2005. REFERENCES Andreassi MG, Botto N. 2003. DNA damage as a new emerging risk factor in atherosclerosis atherosclerosis (ăth'ərōsklərō`sĭs): see arteriosclerosis. atherosclerosis or hardening of the arteries . 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Effect of laboratory protocol, scoring criteria, and host factors on the baseline frequency of micronuclei. Environ Mol Mutagen 37:31-45. Bonassi S, Ugolini D, Kirsch-Volders M, Stromberg U, Vermeulen R, Tucker JD. 2005. Human population studies with cytogenetic biomarkers: review of the literature and future prospectives. Environ Mol Mutagen 54:258-270. Bonassi S, Znaor A, Norppa H, Hagmar L. 2004. Chromosomal aberrations Noun 1. chromosomal aberration - any change in the normal structure or number of chromosomes; often results in physical or mental abnormalities chromosomal anomaly, chromosonal disorder, chrosomal abnormality and risk of cancer in humans: an epidemiological perspective. Cytogen Genome Res 104:376-382. Da Cruz AD, McArthur AB, Silva CO, Curada MP, Glickman BW. 1994. 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(stable form) 5.73; valence −3, 0, +3, or +5. in drinking water drinking water supply of water available to animals for drinking supplied via nipples, in troughs, dams, ponds and larger natural water sources; an insufficient supply leads to dehydration; it can be the source of infection, e.g. leptospirosis, salmonellosis, or of poisoning, e.g. . Mutat Res 370:151-158. Fellay-Reynier I, Orsiere T, Sari-Minodier I, Auquier P, Zattara-Cannoni 14, Capodano M, et al. 2000. Evaluation of micro-nucleated lymphocytes, constitutional karyotypes and anti-p53 antibodies in 21 children with various malignancies. Mutat Res 467:31-39. Fenech M, Chang WP, Kirsch-Volders M, Holland N, Bonassi S, Zeiger E. 2003. HUMN Project: detailed description of the scoring criteria for the cytokinesis-block micronucleus assay using isolated lymphocyte lymphocyte: see blood; immunity. lymphocyte Type of leukocyte fundamental to the immune system, regulating and participating in acquired immunity. 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Down syndrome affects about 1 in every 730 live births and occurs in all populations equally. and Fanconi anemia Fanconi anemia (FA) is a genetic disease that affects children and adults from all ethnic backgrounds. The disease is named after the Swiss pediatrician who originally described this disorder, Guido Fanconi. assessed by micronucleus analysis and single-cell gel electrophoresis gel electrophoresis n. Electrophoresis performed in a gel composed of agarose, polyacrylamide, or starch. . Cancer Genet genet: see civet. Cytogenet 124:71-75. Migliore L, Guidotti P, Favre C, Nardi M, Sessa MR, Brunori E. 1991. Micronuclei in lymphocytes of young patients under antileukemic therapy. Murat Res 263:243-248. Mikhalevich LS, De Zwart FA, Perepetskaya GA, Chebotareva NV, Mikhalevich EA, Tates AD. 2000. Radiation effects in lymphocytes of children living in a Chernobyl contaminated contaminated, v 1. made radioactive by the addition of small quantities of radioactive material. 2. made contaminated by adding infective or radiographic materials. 3. an infective surface or object. region of Belarus. Int J Radiat Biol 76:1377-1385. Neri M, Bonassi S, Knudsen LE, Sram R, Holland N, Ugolini D, et al. 2005a. Children's exposure to environmental pollutants environmental pollutants, n.pl the substances and conditions, including noise, that adversely affect the health and well-being of the people within a community. and biomarkers of genetic damage. I. Overview and critical issues. Murat Res doi: 10.1016/j.mrrev.2005.04.001. Neri M, Fucic A, Knudsen LE, Lando C, Merlo F, Bonassi S. 2003. Micronuclei frequency in children exposed to environmental mutagens: a review. Mutat Res 544:243-254. Neri M, Ugolini D, Bonassi S, Fucic A, Holland N, Knudsen LE, et al. 2005b. Children's exposure to environmental pollutants and biomarkers of genetic damage. II. Results of a comprehensive literature search and meta-analysis. Mutat Res doi: 10.1016/j.mrrev.2005.04.003. Shi Q, Chen J, Adler I, Zhang J, Martin R, Pan S, et al. 2000. Increased non-disjunction of chromosome 21 with age in human peripheral lymphocytes. Mutat Res 452:27-36. Suk WA, Murray K, Avakian MD. 2093. Environmental hazards to children's health in the modern world. Mutat Res 544:235-242. Taioli E, Bonassi S. 2002. Methodological issues in pooled analysis of biomarkers studies. Mutat Res 512:85-92. Tucker JD, Preston RJ. 1996. Chromosome aberrations, micronuclei, aneuploidy, sister chromatid exchanges and cancer risk assessment. Murat Res 365:147-159. Vleminckx C, Klemans W, Schriewer L, Joris I, Lijsen N, Ottogali M, et al. 1997. Performance of cytogenetic biomarkers on children exposed to environmental pollutants. Toxicol Ind Health 13:219-230. Wild CP, Kleinjans J. 2003. Children and increased susceptibility to environmental carcinogens Carcinogens Substances in the environment that cause cancer, presumably by inducing mutations, with prolonged exposure. Mentioned in: Colon Cancer, Rectal Cancer : evidence or empathy? Cancer Epidemiol Biomarkers Prey 12:1389-1394. Zotti-Martelli L, Migliore L, Panasiuk G, Barale R. 1999. Micronucleus frequency in Gomel (Belarus) children affected and not affected by thyroid cancer Thyroid Cancer Definition Thyroid cancer is a disease in which the cells of the thyroid gland become abnormal, grow uncontrollably, and form a mass of cells called a tumor. . Mutat Res 440:3543. Monica Neri, (1,2) Marcello Ceppi, (3) Lisbeth E. Knudsen, (2) Domenico Franco Merlo, (1) Roberto Barale, (4) Riccardo Puntoni, (1) and Stefano Bonassi (3) (1) Unit of Epidemiology and Biostatistics biostatistics /bio·sta·tis·tics/ (-stah-tis´tiks) biometry. bi·o·sta·tis·tics n. The science of statistics applied to the analysis of biological or medical data. , National Cancer Research Institute, Genoa Genoa (jĕn`ōwə), Ital. Genova, city (1991 pop. 678,771), capital of Genoa prov. and of Liguria, NW Italy, on the Ligurian Sea. , Italy; (2) Institute of Public Health, University of Copenhagen The University of Copenhagen (Danish: Københavns Universitet) is the oldest and largest university and research institution in Denmark. , Copenhagen, Denmark; (3) Unit of Molecular Epidemiology, National Cancer Research Institute, Genoa, Italy; (4) Dipartimento di Scienze dell'Uomo e dell'Ambiente, University of Pisa The University of Pisa (Italian Università di Pisa) is one of the most renowned Italian universities. It is located in Pisa, Tuscany. It was formally founded on the September 3, 1343 by an edict of Pope Clement VI, although there had been lectures on law in Pisa since the , Pisa, Italy Address correspondence to S. Bonassi, Unit of Molecular Epidemiology, National Cancer Research Institute, Largo Largo, town (1990 pop. 65,674), Pinellas co., W Fla., on the Pinellas peninsula and the Gulf Coast, across the bay from Tampa; settled 1853, inc. 1905. It is a packing, canning, and shipping center in a citrus fruit and fishing area. Rosanna Benzi 10, 16132 Genoa, Italy. Telephone: 39-010-5600924. Fax: 39-010-5600501. E-mail: stefano.bonassi@istge.it
Table 1. Field studies of MN in children included in the
meta-analysis.
No. of referent children
Reference (total no. of subjects in study)
Shi et al. 2000 20 (68)
Barale et al. 1998 136 (1,650)
Zotti-Martelli et al. 1999 30 (72)
Fellay-Reynier et al. 2000 20 (41)
Vleminckx et al. 19976 33 (220)
31 (220)
25 (220)
Migliore et al. 1991 15 (45)
Maluf and Erdtmann 2001 30 (74)
Livingston et al. 1997 31 (80)
Dulout et al. 1996 12 (44)
Da Cruz et al. 1994 16 (276)
Bilban and Vaupotic 2001 20 (105)
Fenech et al. 1997 11 (116)
Mikhalevich et al. 2000 10 (30)
Meta-estimate 440 (3,261)
MN
Reference (mean [+ or -] SD)
Shi et al. 2000 1.70 [+ or -] 1.83
Barale et al. 1998 2.20 [+ or -] 2.22
Zotti-Martelli et al. 1999 2.26 [+ or -] 2.35
Fellay-Reynier et al. 2000 2.71 [+ or -] 2.60
Vleminckx et al. 19976 2.94 [+ or -] 2.46
4.19 [+ or -] 3.50
4.76 [+ or -] 5.00
Migliore et al. 1991 4.14 [+ or -] 1.75
Maluf and Erdtmann 2001 4.65 [+ or -] 2.25
Livingston et al. 1997 5.16 [+ or -] 2.51
Dulout et al. 1996 5.58 [+ or -] 5.51
Da Cruz et al. 1994 7.33 [+ or -] 3.88
Bilban and Vaupotic 2001 9.00 [+ or -] 3.80
Fenech et al. 1997 9.80 [+ or -] 3.32
Mikhalevich et al. 2000 9.92 [+ or -] 2.70
Meta-estimate 4.48 [+ or -] 0.66 (c)
Age range
Reference (years)
Shi et al. 2000 0-10
Barale et al. 1998 0-19
Zotti-Martelli et al. 1999 15 [+ or -] 2.0 (a)
Fellay-Reynier et al. 2000 0-18
Vleminckx et al. 19976 6-15
6-14
6-15
Migliore et al. 1991 1-12
Maluf and Erdtmann 2001 0-17
Livingston et al. 1997 4-14
Dulout et al. 1996 8-14
Da Cruz et al. 1994 1-18
Bilban and Vaupotic 2001 8-12
Fenech et al. 1997 12-15
Mikhalevich et al. 2000 14-17
Meta-estimate 0-19
(a) Mean [+ or -] SD. (b) Three independently selected groups of
referent children were included in the study (see "Materials and
Methods" for details). (c) SE approximate.
Table 2. Field studies of MN in children included in the pooled
analysis and crude pooled estimates.
No. of MN
Author referents (mean [+ or -] SD)
Barale (HUMN) 119 2.43 [+ or -] 2.39
Fellay-Reynier et al. 2000 20 2.71 [+ or -] 2.60
Migliore et al. 1991 15 4.14 [+ or -] 1.75
Maluf and Erdtmann 2001 30 4.65 [+ or -] 2.24
Dulout et al. 1996 12 5.58 [+ or -] 5.47
Garcia (HUMN) 19 5.63 [+ or -] 3.32
Da Cruz et al. 1994 16 7.33 [+ or -] 3.88
Vorobtsova (HUMN) 8 7.38 [+ or -] 3.07
Chang et al. (HUMN) 54 8.54 [+ or -] 7.71
Scarfi et al. (HUMN) 22 9.44 [+ or -] 3.89
Mikhalevich et al. 2000 10 9.92 [+ or -] 2.70
Muller et al. (HUMN) 7 10.29 [+ or -] 9.76
Crude pooled estimate 332 5.23 [+ or -] 5.07
Age range Males
Author Range (years) (%)
Barale (HUMN) 0.00-10.07 9-18 56
Fellay-Reynier et al. 2000 0.00-6.78 0-18 30
Migliore et al. 1991 1.88-7.53 1-12 40
Maluf and Erdtmann 2001 1.50-12.00 0-17 60
Dulout et al. 1996 0.00-19.00 8-14 25
Garcia (HUMN) 0.00-10.00 7-15 32
Da Cruz et al. 1994 1.00-18.00 1-18 44
Vorobtsova (HUMN) 2.00-12.00 9-17 38
Chang et al. (HUMN) 1.12-49.30 0-17 57
Scarfi et al. (HUMN) 3.68-19.19 0-18 45
Mikhalevich et al. 2000 5.77-14.00 14-17 40
Muller et al. (HUMN) 3.00-31.00 7-14 14
Crude pooled estimate 0.00-49.30 0-18 49
HUMN, data from the HUMN database (Bonassi et al. 2001).
Table 3. Pooled analysis: estimated mean values of MN by sex and age
group (random-effects model) and pooled estimates adjusted by sex
and age.
Females Males
Estimated mean Estimated mean
Age (years) No. (95% CI) No. (95% CI)
<1 25 3.21 (2.17-4.76) 26 3.40 (2.26-5.10)
1-4 13 5.34 (3.41-8.36) 8 5.64 (3.56-8.96)
5-9 27 5.47 (3.82-7.82) 22 5.78 (4.03-8.29)
10-14 54 5.88 (4.23-8.16) 52 6.21 (4.44-8.68)
15-18 51 6.90 (4.86-9.82) 54 7.30 (5.11-10.4)
Pooled 170 5.54 (4.13-7.4) 162 5.94 (4.39-8.04)
Pooled
Estimated mean
Age (years) No. (95% CI)
<1 51 3.27 (2.22-4.82)
1-4 21 5.43 (3.48-8.48)
5-9 49 5.62 (3.97-7.96)
10-14 106 6.02 (4.37-8.30)
15-18 105 7.05 (5.01-9.94)
Pooled 332 5.70 (4.29-7.56)
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