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Published at www.nejm.org May 7, 2008=20 (10.1056/NEJMoa0708698) =

Chromosome 6p22 Locus Associated with Clinically Aggressive=20 Neuroblastoma
John M. Maris, M.D., Yael P. Mosse, M.D., = Jonathan P.=20 Bradfield, B.S., Cuiping Hou, B.S., Stefano Monni, Ph.D., Richard H. = Scott,=20 M.B., B.S., Shahab Asgharzadeh, M.D., Edward F. Attiyeh, M.D., Sharon J. = Diskin,=20 Ph.D., Marci Laudenslager, B.S., Cynthia Winter, B.A., Kristina A. Cole, = M.D.,=20 Ph.D., Joseph T. Glessner, M.S., Cecilia Kim, B.A., Edward C. = Frackelton, B.A.,=20 Tracy Casalunovo, M.S., Andrew W. Eckert, M.S., Mario Capasso, Ph.D., = Eric F.=20 Rappaport, Ph.D., Carmel McConville, Ph.D., Wendy B. London, Ph.D., = Robert C.=20 Seeger, M.D., Nazneen Rahman, M.D., Ph.D., Marcella Devoto, Ph.D., = Struan F.A.=20 Grant, Ph.D., Hongzhe Li, Ph.D., and Hakon Hakonarson, M.D., Ph.D.=20

 
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ABSTRACT

Background Neuroblastoma is a = malignant=20 condition of the developing sympathetic nervous system that = most=20 commonly affects young children and is often lethal. Its = cause is not=20 known.

Methods We performed a genomewide association study by = first=20 genotyping blood DNA samples from 1032 patients with = neuroblastoma=20 and 2043 control subjects of European descent using the = Illumina=20 HumanHap550 BeadChip. Samples from three independent groups = of=20 patients with neuroblastoma (a total of 720 patients) and = 2128=20 control subjects were then genotyped to replicate significant=20 associations.

Results We observed a significant association between=20 neuroblastoma and the common minor alleles of three = consecutive=20 single-nucleotide polymorphisms (SNPs) at chromosome band = 6p22 and=20 containing the predicted genes FLJ22536 and = FLJ44180=20 (P=3D1.71x10=969 = to=20 7.01x10=9610; allelic = odds ratio,=20 1.39 to 1.40). Homozygosity for the at-risk G allele of the = most=20 significantly associated SNP, rs6939340, resulted in an = increased=20 likelihood of the development of neuroblastoma (odds ratio, = 1.97; 95%=20 confidence interval, 1.58 to 2.45). Subsequent genotyping of = the=20 three 6p22 SNPs in three independent case series confirmed = our=20 observation of an association (P=3D9.33x10=9615 at rs6939340 for joint = analysis). Patients with neuroblastoma who were homozygous = for the=20 risk alleles at 6p22 were more likely to have metastatic = (stage=20 4) disease (P=3D0.02), amplification of the MYCN = oncogene in=20 the tumor cells (P=3D0.006), and disease relapse = (P=3D0.01).

Conclusions A common genetic variation at chromosome band = 6p22=20 is associated with susceptibility to neuroblastoma.

Despite marked improvements in the cure rates for many childhood=20 cancers, neuroblastoma remains an important clinical problem, = accounting for 15% of the deaths attributable to malignant = conditions=20 in children.1= =20 It is the most common solid cancer of early childhood, and=20 approximately half of all patients with neuroblastoma present = with=20 widely disseminated disease that is often refractory to = intensive=20 chemoradiotherapy. Cure rates among these high-risk patients = remain=20 less than 40%, despite dramatic increases in the intensity of = chemoradiotherapy, and survivors often have serious lifelong=20 coexisting conditions.2= ,3= ,4= =20

Somatically acquired genomic aberrations in neuroblastoma are = of=20 fundamental importance for predicting the tumor phenotype in=20 patients.1= =20 Tumors with amplification of the MYCN oncogene or = deletions of=20 the chromosome arms 1p, 11q, or both, typically are = metastatic at=20 diagnosis and resistant to therapy.5= =20 Conversely, tumors showing no structural chromosomal changes = but=20 hyperdiploidy due to whole-chromosome gains are more easily = cured and=20 may even spontaneously regress.6= =20

Neuroblastoma is an embryonal cancer; it is thought to arise = from=20 partially committed primordial cells during fetal or early = childhood=20 development. Despite the wealth of knowledge about = somatically=20 acquired genomic aberrations that correlate with tumor = phenotype,=20 little is known about the events that predispose to the = development=20 of neuroblastoma. Epidemiologic studies have not identified a = common=20 environmental exposure that influences susceptibility to=20 neuroblastoma,7= ,8= ,9= =20 and genetic studies of hereditary disease have been hampered = by the=20 rarity of the condition and the small size of pedigrees due = to the=20 lethality of neuroblastoma in early childhood.= 10=20 A family history of neuroblastoma is obtained in only about = 1% of=20 patients,= 11=20 and studies of such families suggest locus heterogeneity; no = commonly=20 mutated gene has been identified.= 12,= 13,= 14=20 We therefore hypothesized that neuroblastomas arise from = relatively=20 common DNA variations that predispose to an increased risk of = neuroblastic malignant transformation.

Methods

Subjects

For genomewide genotyping, case subjects were defined as = children=20 with a diagnosis of neuroblastoma or ganglioneuroblastoma and = registered through the Children's Oncology Group. The blood=20 samples from the patients with neuroblastoma were identified=20 through the neuroblastoma biorepository of the Children's = Oncology=20 Group for specimen collection at the time of diagnosis. The=20 majority of specimens were annotated with clinical and = genomic=20 information that included the patient's age at diagnosis, = site=20 of tumor origin, disease stage according to the International = Neuroblastoma Staging System,= 15=20 International Neuroblastoma Pathology Classification,= 16=20 MYCN oncogene copy number,= 17=20 DNA index (i.e., ploidy status),= 18=20 registration in a clinical trial or clinical trials, = event-free and=20 overall survival, second tumors, and any associated = conditions (e.g.,=20 congenital abnormalities).

The eligibility criterion for genomewide genotyping was the=20 availability of 1.5 =B5g of DNA of high quality from a = tumor-free=20 source such as peripheral blood or bone marrow mononuclear = cells=20 that were uninvolved with a tumor. Because neuroblastoma in = the=20 United States most often occurs in persons of European descent,= 19=20 we limited our initial analyses to the DNA samples from the=20 blood of such persons to minimize genetic variability. We = randomly=20 divided subjects with samples dedicated to genomewide testing = into a group of 1251 case subjects for the discovery phase = and=20 a group of 409 case subjects for an initial replication = phase.

Control subjects were recruited from the Philadelphia region=20 through the Children's Hospital of Philadelphia Health Care=20 Network, including four primary care clinics and several = group=20 practices and outpatient practices that included well-child=20 visits. Eligibility criteria for control subjects were = European=20 ancestry as determined by self-report or parental report,=20 availability of 1.5 =B5g of high- quality DNA from = peripheral-blood=20 mononuclear cells, and no serious underlying medical = disorder,=20 including cancer. The median age of the control subjects at = the time=20 of sample collection was 10.0 years. We genotyped=20 single-nucleotide polymorphisms (SNPs) across the genomes of = 3414=20 control subjects and randomly assigned 2236 subjects to the = discovery=20 phase and 1178 to the initial replication phase.

Two additional case series were used for the purpose of = replication.=20 First, 252 randomly selected and unrelated patients with=20 neuroblastoma or ganglioneuroblastoma were recruited from = pediatric=20 oncology centers in the United Kingdom either as part of a = group of=20 patients who had received a diagnosis of neuroblastoma at the = Birmingham Children's Hospital since 1992, through the = Factors=20 Associated with Childhood Tumours study, or from the Tumour = and=20 Leukaemia Bank of the Childhood Cancer and Leukaemia Group. A = total=20 of 788 samples from control subjects were obtained from the = 1958=20 Birth Cohort collection, an ongoing follow-up study of all = persons=20 born in Britain during 1 week in 1958, including a recent = biomedical=20 assessment during the period from 2002 through 2004; during=20 this assessment, blood samples and written informed consent=20 were obtained for the creation of a genetic resource (the = National=20 Child Developmental Study, www.cls.ioe.ac.uk/). All case = subjects=20 and control subjects were from the United Kingdom, and = subjects=20 known to be of non-European ancestry were excluded. The final = replication group of 59 unrelated persons with high-risk=20 neuroblastoma were recruited from the U.S.-based Children's = Cancer=20 Group protocols from the 1990s.2= =20 Control DNA samples from the Children's Cancer Group were = derived=20 from buccal swabs (obtained for the creation of an anonymized = genetic=20 resource) from 162 unrelated persons of European descent = living in=20 the Los Angeles area during the period from 2000 through = 2001.=20

Written informed consent was obtained from all participants, = and=20 the study was approved by each participating center's institutional = review board as well as by the Scientific Council and the=20 Neuroblastoma Disease Committee of the Children's Oncology = Group and=20 the Cancer Therapy Evaluation Program at the National Cancer=20 Institute.

Genotyping

Details of methods for genomewide genotyping have been described = elsewhere.= 20,= 21=20 Descriptions of these methods, along with methods for = replication=20 genotyping by means of polymerase chain reaction=96based = allelic=20 discrimination assays, are included in the Suppl= ementary=20 Appendix, available with the full text of this article at = www.nejm.org.

Statistical Analysis

Genomewide genotyping data from an initial 1251 patients with=20 neuroblastoma and 2236 disease-free control subjects in the=20 discovery phase were filtered on the basis of prespecified=20 quality-control measures. Individual SNPs were excluded from = further=20 analysis if they showed deviation from the Hardy=96Weinberg=20 equilibrium with a P value of less than 0.001, an individual = SNP=20 genotype yield of less than 98%, or a minor allele frequency = of=20 less than 5%. This filtering resulted in the use of 464,934 = SNPs=20 in the subsequent analyses. A total of 33 samples (from 23 = case=20 subjects and 10 control subjects) had genotype yields of less = than 90% and were removed. Because the case samples were = accrued=20 nationwide, whereas the control set was recruited locally in=20 Philadelphia, we performed principal-components analyses to=20 identify outlier samples to reduce the effects of population=20 stratification.= 22,= 23=20 These analyses resulted in the removal of 379 samples (from = 196 case=20 subjects and 183 control subjects), resulting in 1032 = patients and=20 2043 control subjects for our discovery-phase case series. = Evaluation=20 of these 3075 subjects with the use of ancestry informative = markers=20 available on the HumanHap550 BeadChip indicated European = ancestry in=20 all but 2 subjects; these 2 subjects remained in the = analysis.= 24=20 The patients with neuroblastoma were representative of the=20 expected distribution of clinical and biologic covariates as=20 observed in patients with neuroblastoma in the general = population=20 (Table S1 in the Suppl= ementary=20 Appendix).1= ,= 19=20

The primary statistical tests for association in the = discovery-phase=20 case series were carried out with the use of the PLINK = software=20 package.= 25=20 We conservatively set 1.0x10=967 as=20 the threshold for genomewide significance, on the basis of = the fact=20 that slightly less than 500,000 SNPs were used in the = analysis=20 (0.05=F7500,000=3D1.0x10=967).=20 The single-marker analyses for the genomewide data were = carried=20 out with the use of the chi-square test on the basis of = differences=20 in allele counts between 1032 case subjects and 2043 control=20 subjects and the Cochran=96Armitage test for trends on = genotype=20 frequencies. Allelic odds ratios and the corresponding 95% = confidence=20 intervals were calculated for the association analyses. In = addition,=20 to further control for the potential confounding influence of = population stratification, we performed association analyses=20 after correction for substructure based on a = principal-components=20 analysis as implemented in Eigenstrat.= 22,= 23=20 For each SNP, we used the default settings within the program = and=20 performed a modified Cochran=96Armitage trend test adjusting = for=20 the top five principal components,= 22,= 23=20 and we report the result as the Eigenstrat P value. Fig. S1 = in the Suppl= ementary=20 Appendix shows quantile=96quantile plots before and after = correction.

Of the 1032 patients included in the discovery-phase case = series,=20 clinical and biologic covariate data obtained at diagnosis = were=20 available for most (Table S1 in the Suppl= ementary=20 Appendix). Complete outcome data were available for 883 = patients=20 (85.6%), with a median follow-up interval of 4.02 years for=20 patients without an event. Association analyses of chromosome = 6p22=20 SNPs with clinical characteristics were performed with the=20 chi-square test on allele and genotype counts. These analyses = were=20 also performed for outcome by comparing Kaplan=96Meier = survival=20 curves by means of the log-rank test in a pairwise fashion. =

Results

To identify sequence variants that are associated with = susceptibility=20 to the development of neuroblastoma, we compared = single-marker=20 allele and genotype frequencies in our discovery-phase case=20 series, using statistics based on chi-square analysis and the = Cochran=96Armitage trend test. The Eigenstrat-corrected = summary=20 statistics for the full data set are available in the = repository of=20 the National Institutes of Health Genotype and Phenotype = database=20 (dbGAP; www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi= ?study_id=3Dphs000124.v1.p1)=20 (accession number, phs000124.v1.p1). The top three SNPs = showing=20 a significant association to neuroblastoma were in close = linkage=20 disequilibrium at chromosome 6p22 (rs6939340, rs4712653, and=20 rs9295536) yielding P values of 1.71x10=969 to 7.01x10=9610 (allelic = odds ratio,=20 1.39 to 1.40) (Figure= 1=20 and Table = 1, and Table S2 in the Suppl= ementary=20 Appendix). Two additional SNPs at chromosome 20p11 = (rs3790171 and=20 rs7272481) showed genomewide significant single-marker P = values, and=20 many others were very close to the genomewide significance = threshold=20 (Figure= =20 1). However, only the chromosome 6 association-study = results=20 retained genomewide significance after further correction for = population substructure with the use of principal-components = analyses=20 as implemented in Eigenstrat= 22,= 23=20 (Table = 1). The signal on chromosome 6 falls within a 94.2-kb=20 linkage-disequilibrium block containing the predicted = overlapping=20 genes FLJ22536 and FLJ44180 (Figure= =20 2).


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  		Figure 1. = Results=20 of the Discovery Phase of the Neuroblastoma Genomewide = Association=20 Study.

The y axis represents the level of significance for each=20 single-nucleotide polymorphism (log-transformed P values) at = the=20 relative genomic position on each chromosome along the x = axis from=20 the short-arm terminus (left) to the long-arm terminus = (right). The=20 black line indicates the genomewide significance threshold. =

 
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  		Table 1. = Results=20 of the Discovery Phase of a Neuroblastoma Genomewide = Association=20 Study for Case and Control Subjects. =

 

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  		Figure 2. = Pairwise=20 Linkage Disequilibrium (LD) Plot of the 6p22 Locus and = Results of=20 the Association Analyses for Regional Single-Nucleotide=20 Polymorphisms (SNPs).

The diagram shows a 290.98-kb region from rs12207699 to=20 rs9393266, with pairwise LD calculated from the = discovery-phase case=20 and control data sets combined (as measured by the LD = coefficient=20 D'). Individual SNP log-transformed P values are plotted in = relation=20 to the LD diagram, which was created with the use of = Haploview=20 software.= 26=20 The three SNPs showing a genomewide significant-association = signal=20 (red horizontal line) are annotated (r2 was 0.873 = for=20 SNPs rs4712653 and rs9295536 and 0.731 for SNPs rs9295536 = and=20 rs6939340) and map within a 94.2-kb LD block, delimited by = SNPs=20 rs196051=20 and rs10498705 (dashed vertical lines). All SNPs are also = annotated=20 to their relative positions on the physical map (based on = the=20 National Center for Biotechnology Information database, = build 36),=20 with predicted genes in the region shown (exons and = transcribed=20 sequences are indicated by solid vertical lines). =

 
We = next=20 sought to replicate the association signals of chromosomes = 6p22 and=20 20p11 in three separate pairings of patients with neuroblastoma = and=20 control subjects. As shown in Table = 2,=20 the risk alleles in chromosome 6 identified in the discovery = phase=20 were also significantly overrepresented in all three groups = of=20 patients with neuroblastoma as compared with control = subjects,=20 yielding a combined P value and allelic odds ratio for the = most=20 strongly associated SNP rs6939340 of 9.33x10=9615 and 1.37, = respectively=20 (95% confidence interval, 1.27 to 1.49). We did not observe=20 replication of the association between the alleles in = chromosome=20 20 and neuroblastoma (identified in the discovery cohort) in=20 the three replication case series (Table S3 in the Suppl= ementary=20 Appendix).

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  		Table 2. = Results=20 of Replication Studies of the Chromosome 6 Association. =

 
To=20 determine whether the three implicated SNPs at the chromosome = 6p22=20 locus were differentially associated with patient subgroups = and=20 outcome, we analyzed their prevalence according to prognostically=20 relevant clinical and biologic covariates present at = diagnosis=20 and survival rates among patients in the case series from the = Children's Oncology Group. All three SNPs were associated = with=20 a more malignant clinical presentation and aggressive disease = course (Figure= 3).=20 Accordingly, tumors that were metastatic at diagnosis were = more=20 likely to develop in patients with neuroblastoma who were = homozygous=20 for the at-risk alleles (P=3D0.006, P=3D0.008, and P=3D0.024 = for rs4712653,=20 rs9295536, and rs6939340, respectively), to have somatically = acquired=20 amplification of the MYCN oncogene in tumor cells = (P=3D0.002,=20 P=3D0.003, and P=3D0.006, respectively), and to have a = high-risk=20 classification for the purposes of treatment stratification = (P=3D0.002,=20 P=3D0.001, and P=3D0.011, respectively), as compared with = patients with=20 neuroblastoma who were homozygous for the alleles that were = not=20 associated with risk (Table S4 and S5 in the Suppl= ementary=20 Appendix). In addition, patients who were homozygous for = the risk=20 alleles had a significantly decreased probability of = event-free=20 survival (P=3D0.016 for SNP rs6939340) (Fig. S2 in the Suppl= ementary=20 Appendix). This association with more malignant disease = may=20 explain why we were able to show replication of results in = the=20 relatively small series of 59 patients from the Children's = Cancer=20 Group that consisted solely of high-risk patients (Table = 2).


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  		Figure 3. = Risk=20 Alleles at Chromosome 6p22 Associated with a More Malignant=20 Neuroblastoma Phenotype.

Frequency distributions of genotypes (homozygous G [GG],=20 heterozygous AG, or homozygous A [AA]) of patients = classified=20 according to three clinical variables and of control = subjects are=20 shown for single-nucleotide polymorphism (SNP) rs6939340, = along with=20 P values of allelic tests between the clinical subgroups and = between=20 each of them and the controls. Similar results were obtained = for=20 SNPs rs4712653 and rs9295536. Specifically, patients = assigned to a=20 high-risk group (Panel A), with tumors that harbor = MYCN=20 amplification (Panel B), and with stage 4 disease (Panel C) = were=20 more likely to be homozygous for the risk allele C at = rs4712653, A=20 at rs9295536, and G at rs6939340 (see Tables S4 and S5 in = the Suppl= ementary=20 Appendix). =

 
Discussion

This study shows that the likelihood for malignant = transformation=20 of developing neuroblasts is influenced by variants on = chromosome=20 6p22. Associations between neuroblastoma and other loci may=20 come to light as we continue toward our goal of the = genomewide=20 genotyping of DNA samples from 5000 patients with = neuroblastoma.=20 Our data provide support, on a preliminary level, for the = "common=20 variant, common disease" model for neuroblastoma (i.e., the=20 interaction of multiple relatively common genetic variations = in=20 the developing neuroblast may predispose toward the development = of=20 the disease).

The motivation for this large and ongoing study was the paucity = of=20 information on neuroblastoma tumorigenesis. Our study provides=20 proof-of-concept results for a genomewide-association = approach=20 to neuroblastoma and identifies new candidate susceptibility=20 genes, although little is known about these genes. = FLJ22536=20 has multiple predicted isoforms and contains a potential = epidermal=20 growth factor=96like domain. The FLJ44180 has no = sequence=20 similarities in human or mouse nucleic acids and protein = databases.=20 Studies are under way to determine how the presence of common = DNA variants at 6p22 contributes to the risk of neuroblastic=20 malignant transformation and the subphenotype of high-risk = disease.=20

Supported by the efforts of multiple investigators=20 throughout the Children's Oncology Group (U10-CA98543, Dr. = Gregory=20 Reaman, chair); grants (R01-CA78454, to Dr. Maris; = R01-ES009911,=20 to Dr. Li; and R01-CA60104, to Dr. Seeger) from the National=20 Institutes of Health, the Alex's Lemonade Stand Foundation = (to Dr.=20 Maris), the Center for Applied Genomics at the Joseph Stokes = Jr.=20 Research Institute, which funded all genomewide association=20 genotyping (to Dr. Hakonarson), the Abramson Family Cancer = Research=20 Institute (to Dr. Maris), the Neuroblastoma Society (to Drs. = Rahman=20 and Scott), and the Institute of Cancer Research (to Drs. = Rahman=20 and Scott); a fellowship from the Associazione Italiana per = la=20 Ricerca sul Cancro (to Dr. Capasso); and the Factors Associated = with=20 Childhood Tumours Study and the Tumour and Leukaemia Bank of = the=20 Childhood Cancer and Leukaemia Group. DNA was provided by the = British=20 1958 Birth Cohort collection, funded by grants from the = Medical=20 Research Council (G0000934) and from the Wellcome Trust=20 (068545/Z/02).

No potential conflict of interest relevant to this article was=20 reported.


Source Information

From the Division of Oncology and the Center for = Childhood=20 Cancer Research (J.M.M., Y.P.M., C.H., E.F.A., S.J.D., M.L., C.W., = K.A.C.,=20 E.F.R.), the Center for Applied Genomics ( J.P.B., J.T.G., C.K., E.C.F., = T.C.,=20 A.W.E., S.F.A.G., H.H.), and the Division of Genetics (M.C., M.D., = S.F.A.G.,=20 H.H.), Children's Hospital of Philadelphia; and the Department of = Pediatrics=20 (J.M.M., Y.P.M., C.H., E.F.A., S.J.D., M.L., C.W., K.A.C., E.F.R.), the = Abramson=20 Family Cancer Research Institute, (J.M.M.), the Department of = Biostatistics and=20 Epidemiology (S.M., M.D., H.L.), and the Department of Pediatrics (M.C., = M.D.,=20 S.F.A.G., H.H.), University of Pennsylvania School of Medicine =97 all = in=20 Philadelphia; the Section of Cancer Genetics, Institute of Cancer = Research,=20 Sutton, Surrey, United Kingdom (R.H.S., N.R.); the Division of=20 Hematology=96Oncology and the Saban Research Institute, Children's = Hospital Los=20 Angeles, and the Keck School of Medicine, University of Southern = California =97=20 both in Los Angeles (S.A., R.C.S.); Federico II University, Centro di = Ingegneria=20 Genetica Biotecnologie Avanzate, Naples, Italy (M.C.); the Division of=20 Reproductive and Child Health and CRUK Institute for Cancer Studies, = University=20 of Birmingham, Birmingham, United Kingdom (C.M.); the Department of = Statistics,=20 University of Florida, and the Children's Oncology Group =97 both in = Gainesville=20 (W.B.L.); and the Department of Experimental Medicine, La Sapienza = University of=20 Rome, Rome (M.D.).

Dr. Mosse and Mr. = Bradfield=20 contributed equally to this article.

This = article=20 (10.1056/NEJMoa0708698) was published at www.nejm.org on May 7, 2008. It = will=20 appear in the June 12 issue of the Journal.

Address reprint requests to Dr. Maris at the = Children's=20 Hospital of Philadelphia, 907A, 3516 Civic Center Blvd., Philadelphia, = PA=20 19104-4318, or at maris{at}chop.edu , or to Dr. Hakonarson at the Children's Hospital of Philadelphia, = ARC12, 3516=20 Civic Center Blvd., Philadelphia, PA 19104-4318, or at hakonarson{at}chop.edu .

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------=_NextPart_000_0000_01C8B0F8.49A865D0 Content-Type: application/octet-stream Content-Transfer-Encoding: quoted-printable Content-Location: http://survey.nejm.org/scripts/survey.js function invite(inviteurl,frmWidth,frmHeight,svyName,expire) { //******************************************************************** // Display invitation if specific cookie not found and set cookie // Parameters // inviteurl: URL of invite form // frmWidth & frmHeight: dimensions of invitation window // svyName: Name of the specific survey // expire: Number of days before cookie expires //=20 // Created by Chris Miceli 2/25/2004 //******************************************************************** // define variables var theCookie =3D document.cookie; var today =3D new Date(); var expDate =3D new Date(); // Check if user has visited page before if (theCookie.indexOf(svyName) =3D=3D -1) { =20 expDate =3D whenIs(today, expire); expDate =3D expDate.toGMTString(); document.cookie =3D svyName + "; path=3D/; expires=3D" + expDate + = ";"; window.open(inviteurl, "", "toolbar=3Dno,status=3Dno,width=3D" + = frmWidth + ",height=3D" + frmHeight + ",top=3D150,left=3D50"); //window.open(surveyurl, "", = "toolbar=3Dno,status=3Dno,width=3D270,height=3D220,top=3D150,left=3D50");= } } function invite(inviteurl,frmWidth,frmHeight,svyName,expire,path) { //******************************************************************** // Display invitation if specific cookie not found and set cookie // Parameters // inviteurl: URL of invite form // frmWidth & frmHeight: dimensions of invitation window // svyName: Name of the specific survey // expire: Number of days before cookie expires // path: cookie path //=20 // Created by Chris Miceli 2/25/2004 //******************************************************************** // define variables var theCookie =3D document.cookie; var today =3D new Date(); var expDate =3D new Date(); // Check if user has visited page before if (readCookie(svyName) =3D=3D null) { =09 createCookie(svyName, svyName, expire); window.open(inviteurl, "", "toolbar=3Dno,status=3Dno,width=3D" + = frmWidth + ",height=3D" + frmHeight + ",top=3D150,left=3D50"); } } function whenIs(anyDate, n){ //-- Returns the date that is n days from any date. var newDate =3D new Date(); newDate.setTime(anyDate.getTime()+(n*1000*60*60*24)); return newDate; } //******************************************************************** // Display invitation if specific cookie not found and set cookie // Parameters // Display invitation every nthe hit on page, every 5th customer or = every 163rd customer. =20 // Created by SFungafat , Modified RKumar June 2004 //******************************************************************** function intercept(surveyurl) { // define variables var cookie_ls =3D document.cookie; var date_ls =3D new Date(); var S =3D new Date(); // if not yet sampled if (cookie_ls.indexOf("NEJM062004WEB") =3D=3D -1) { rnd.today=3Dnew Date(); rnd.seed=3Drnd.today.getTime(); =20 function whenIs(anyDate, n){ //-- Returns the date that is n days from any date. var newDate =3D new Date(); = newDate.setTime(anyDate.getTime()+(n*1000*60*60*24)); return newDate; } function rnd() { rnd.seed =3D (rnd.seed*9301+49297) % 233280; return rnd.seed/(233280.0); }; function rand(number) { return Math.ceil(rnd()*number); }; =20 sample=3Drand(5); // for the sample grab 1 in 5 if (sample=3D=3D5) { S =3D whenIs(date_ls, 3); S =3D S.toGMTString(); document.cookie =3D "NEJM062004WEB; path=3D/; expires=3D" + = S + ";"; window.open(surveyurl, "", = "toolbar=3Dno,status=3Dno,width=3D600,height=3D300,top=3D150,left=3D50") } } } //************************************************ // Set pop-up cookie based on country and IP type // Parameters // country: two character country code // instFlag: NEJM Institution, 1=3DTrue, 0=3DFalse // ** Use ISO 3166 standard 2-letter country codes ** //************************************************ function intlSurvey(country, instFlag) { var validCtys =3D "JP"; if (cookiesAreEnabled()) { country =3D country.toUpperCase() =09 // Invite only displayed for valid countries if (country.indexOf(validCtys) > -1) { if (instFlag =3D=3D 1) { //Set cookie one day for NEJM Institutions = invite('http://survey.nejm.org/NEJMJPN/popup.aspx',510,260,'NEJMESINST',1= , 'nejm.org'); } else { //60 days for all others = invite('http://survey.nejm.org/NEJMJPN/popup.aspx',510,260,'NEJMESNONINST= ',45, 'nejm.org'); } =09 } } } //************************************************ // Set pop-up cookie based on country.=20 // Parameters // userCty: Country user from // validCty: Country or countries to test against // inviteurl: URL of invite form // svyName: Name of the specific survey // expire: Number of days before cookie expires // frmWidth & frmHeight: dimensions of invitation window //************************************************ function surveyByCty(userCty, validCty, inviteurl, svyName, expire, = frmWidth, frmHeight) { if (cookiesAreEnabled()) { userCty =3D userCty.toUpperCase() validCty =3D validCty.toUpperCase() =09 // Invite only displayed for valid countries if (userCty.indexOf(validCty) > -1) { //Display invite invite(inviteurl, frmWidth, frmHeight, svyName, expire); } } } // Checks if cookies are enabled in browser. function cookiesAreEnabled() { setCookie( "foo", "bar" ); if ( getCookie( "foo" ) ) { deleteCookie( "foo" ); return true; } else { return false; } } function setCookie( name, value, expires, path, domain, secure ) { document.cookie =3D name + "=3D" + escape (value) + ( ( expires ) ? 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