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Francis at Al 2011

Francis at Al 2011

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Please cite this article in press as: S.S. Francis, et al., Unusual space-time patterning of the Fallon, Nevada leukemia cluster: Evidence of aninfectious etiology, Chem. Biol. Interact. (2011), doi:10.1016/j.cbi.2011.02.019
ARTICLE IN PRESS
GModelCBI-6490; No.of Pages8Chemico-Biological Interactions
xxx (2011) xxx–xxx
Contents lists available atScienceDirect
Chemico-BiologicalInteractions
 journal homepage:www.elsevier.com/locate/chembioint
Unusual space-time patterning of the Fallon, Nevada leukemia cluster:Evidence of an infectious etiology
Stephen S. Francis
a
, Steve Selvin
a
,
b
, Wei Yang
c
, Patricia A. Buffler
a
, Joseph L. Wiemels
d
,
a
Division of Epidemiology, School of Public Health, University of California, Berkeley, United States
b
Division of Biostatistics, School of Public Health, University of California, Berkeley, United States
c
Nevada Center for HealthStatistics and Informatics,University of N evada,Reno, United States
d
Department of Epidemiology and Biostatistics, University of California, San Francisco, United States
a r t i c l e i n f o
 Article history:
Received 2 September 2010Received in revised form 12 February 2011Accepted 16 February 2011
Available online xxx
Keywords:
LeukemiaFallonTungstenVirusMosquitoChildhood
a b s t r a c t
The town of Fallon within Churchill County, Nevada exhibited an unusually high incidence of childhoodleukemiaduringtheyears1997–2003.Weexaminedthetemporalandspatialpatterningoftheleukemiacase homes in comparison to the distribution of the general population at risk, other cancer incidence,and features of land use. Leukemia cases were predominantly diagnosed during the early to mid sum-mer, exhibiting a seasonal bias. Leukemia cases lived outside of the “developed/urban” area of Fallon,predominantly in the “agriculture/pasture” region of Churchill County, circumscribing downtown Fal-lon. This pattern was different from the distribution of the underlying population (
 p
-value<0.01) anddifferent from the distribution of other cancers, which were evenly distributed when compared to thepopulation (
 p
-value=0.74). The unusual space-time patterning of childhood leukemia is consistent withthe involvement of an infectious disease. A possible mode of transmission for such an infectious diseaseis by means of a vector, and mosquitoes are abundant in Churchill County outside of the urban areaof Fallon. This region harbors a US Navy base, and a temporally concordant increase in military widechildhood leukemia rates suggests the base a possible source of the virus. Taken together, our currentunderstanding of the etiology of childhood leukemia, the rural structure combined with temporal andgeospatialpatterningoftheseleukemiacases,andthehighdegreeofpopulationmixinginFallon,suggesta possible infectious cause.
© 2011 Elsevier Ireland Ltd. All rights reserved.
1. Introduction
The etiology of most cases of childhood leukemia is unknown.Apart from a higher incidence among children carrying specificpredisposition genes, the disease is generally unclustered in fami-lies[1]and populations[2,3]. Anecdotal observations of clustering of childhood leukemia have led investigators to hypothesize spe-cific causes of the clusters, ranging from population mixing andunique viruses in naïve populations to chemical exposures frompoint sources[4–13]. A childhood leukemia cluster observed inFallon, Churchill County, Nevada is a striking example of suchclustering. Fourteen children residing in Churchill County werediagnosed with acute lymphoblastic leukemia (ALL) during theperiod1997–2003withmostcasesoccurringin1999and2000[14].Based on the population at risk, only one case would be expectedevery two years, resulting in a risk ratio of 12 for childhood
Corresponding author at: UCSF, HD 274 Mail Code 0520, 1450 3rd Street, SanFrancisco, CA, United States. Tel.: +1 415 514 0577; fax: +1 415 502 7411.
E-mail address:
joe.wiemels@ucsf.edu(J.L. Wiemels).
leukemia if a child resided in Churchill County during 1997–2003[15].Fallon has a distinctive natural and anthropomorphic environ-ment.ThegeologicalbasinwhereFallonislocatedcontainsnaturalarsenic, tungsten, and radioactive minerals including uranium andpolonium[16,17].Thisbasinalsoservesasahydrologicsink,result-inginwetlandsandlandsuitableforabundantagriculturalactivity.Additionally, Fallon incorporates a Navy training facility and a pri-vate hard metal refining facility. While none of these features areby themselves unique, their combination in Fallon focused inves-tigator’s attention on a possible chemical cause for the leukemiaclusterandledtothemostcomprehensivecancerclusterinvestiga-tion in history by the U.S. Center of Diseases Control (CDC)[14,18].A total of 205 individuals including the 14 cases of leukemia andtheirfamiliesand55comparisonfamilieswerestudied
1
.Fivehun-dredbehaviorvariablesassessedbyquestionnaires,alongwith139
1
CDC case definition was comprised of 2 factors: Pre-B ALL and 6 month of resi-denceinChurchillCountypriortodiagnosis.Usingthiscasedefinition15caseswereeligible (14 enrolled).0009-2797/$ – see front matter
© 2011 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.cbi.2011.02.019
 
Please cite this article in press as: S.S. Francis, et al., Unusual space-time patterning of the Fallon, Nevada leukemia cluster: Evidence of aninfectious etiology, Chem. Biol. Interact. (2011), doi:10.1016/j.cbi.2011.02.019
ARTICLE IN PRESS
GModelCBI-6490; No.of Pages8
2
S.S. Francis et al. / Chemico-Biological Interactions
 xxx (2011) xxx–xxx
chemicals tested in samples of blood, urine, cheek cells, soil, andhouse dust, were analyzed. In contrast to the intense scrutiny of chemicals,only4viruseswithpriorassociationswithB-cellmalig-nancies,humanT-lymphotropicvirus(HTLV),felineleukemiavirus(FeLV), avian leukemia virus (ALV), and Epstein Barr virus (EBV)were examined along with a reverse transcriptase activity assay[14].AprimaryfindingintheCDCstudywaselevatedtungstenandarseniclevelsintheurineofbothadultsandchildren,yettheseele-vatedlevelswereobservedequallybetweencaseandcontrolseries[18].We examined the temporal and geospatial organization of theFallon leukemia cases compared to the population of ChurchillCounty and found an unusual patterning of the cases, consistentwith a novel hypothesis.
2. Materials and methods
 2.1. Data sources
Data on the temporal pattern of leukemia for the 15 cases eli-gible for the CDC study were extracted from Center for DiseaseControl (CDC) reports[14]. Incident ALL cases and age-specificpopulation counts were obtained from the Tricare administrativedatabases for years 1996–2005, these data are billing records fromall military service branches from both active and retired servicepersonnel and their dependants. Cancer cases for Churchill Countyfrom the years 1999–2004 and their point locations were obtainedfrom the Nevada Cancer Registry. The year 1999 was used as astartingpoint,astheNevadaCancerRegistryachievedSurveillance,Epidemiology, and End Results (SEER) “gold” status from this yearforward.Estimatesofunderlyingthepopulationaswellasthepop-ulation“atrisk”wereobtainedfromUnitedStatescensusblockdata[19]. These counts demonstrated a reasonably homogenous agedistribution observed within block groups. In addition to humanpopulation data, point (GPS) locations for mosquito traps and theresults of West Nile virus tests from those pooled mosquitoes fortheyear2004wereobtainedfromtheChurchillCountyvectorcon-trol agency. All mapped locations of cancers have been randomlyadjusted, or “jittered”, to maintain confidentiality in figures dis-played in this paper.
 2.2. Analysis
Epidemic curves were plotted by month and compared to pub-lished reports on seasonal trends of childhood leukemia[20–23].Statisticaltestsofseasonalitywerenotperformedduetothesmallsample size. Incident ALL counts were examined in the Tricaredatabase for age groups 0–19. Rates were calculated using age,branch and year specific populations as the denominator. Rateswere age adjusted using a weights calculated from the inversevariance of each observation.All addresses were geocoded and projected to allow compar-isons. The spatial distribution of the Fallon cluster cases wasexaminedusinggeographicinformationsystemsandthestatisticalpackage
R
[24,25]. U.S. census block counts were utilized as esti-mates of the underlying population. Rates within geographic areaswith small numbers are not stable; therefore, special statisticaltechniques, density equalized map projection (DEMP), sometimesreferred to as cartograms, were employed to better represent theunderlying population structure[26]. Cluster locations were com-pared to the Vegetation Synthesis map[27]to assess the land useand vegetation type at each case residential location.A test of variance was usedto examine the spatial distributionsof cases[28]. In this study of spatial patterns of disease, the distri-butionofthepopulationisknownandisbestrepresentedbycensusblocks. The observed distribution of cases was directly comparedto the population distribution to statistically assess the homogenyof observed disease patterns over the population. Cumulative dis-tribution functions (CDF) of sample points and the underlyingpopulation were compared, providing a useful statistical tool tovisually identify exceptional patterns among cases of disease. Inaddition, the mean and variance of the distribution of the sampleofcaseswerecomparedtotheparallelmeanandvariancefromthepopulation providing simple and common statistical measures of observed differences. When the spatial distribution under consid-erationistransformedtoanequaldensitypopulation(asinDEMP),then, the distribution of the population is uniform, and the samplecumulative distribution is a straight line, with an expected meanvalueof0.5andanestimatedmeanvaluewithavariance=1/(12
n
).In addition, the approximate normal distribution of the estimatedsamplehasavariance=1/(180
n
)wherenrepresentsthenumberof casesofdisease.Thetestofthesamplemeanandvarianceprovidesa bivariate evaluation of the likelihood that the observed spatialpattern is not random.
3. Results
 3.1. Temporal trends
Nine of the 15 CDC defined cases occurred from February2000–November 2000[14](Fig. 1A), a notable increase within the overall cluster period. A seasonal trend is suggested when viewingcasesbydiagnosismonth(Fig.1B).Smallsamplesizeprecludedfor-malstatisticaltesting.Tricaredatashowedanincreaseinchildhood ALLratespeakingin1999intheNavy,withalongerpeakobservedfrom 1999–2000in theAir Force and Army (Fig. 2). Observed rates are stable due to the large sample size and a Poisson distribu-tion analysis rejected the null hypothesis of no change in rates(
<0.01). This combined with 3 separateconcurrent observations
Fig. 1.
Temporal pattern of leukemia cases in the Fallon, Nevada leukemia cluster.(A) Timing of leukemia over the five-year period with a notable spike in 2000. (B)Seasonal timing of leukemia cases with most cases between April and July.
 
Please cite this article in press as: S.S. Francis, et al., Unusual space-time patterning of the Fallon, Nevada leukemia cluster: Evidence of aninfectious etiology, Chem. Biol. Interact. (2011), doi:10.1016/j.cbi.2011.02.019
ARTICLE IN PRESS
GModelCBI-6490; No.of Pages8
S.S. Francis et al. / Chemico-Biological Interactions
 xxx (2011) xxx–xxx
3
**********
1996 1998 2000 2002 2004
      1 .      5      2 .      0      2 .      5      3 .      0      3 .      5
Year 
      R    a     t    e      /      1      0      0      0      0      0
oooooooooo++++++++++xxxxxxxxxx*o+x
 All Branchs Army Air ForceNavy
Fig.2.
Ageadjustedacutelymphoblasticleukemia(Age0–19)
.
Casecountsandage,branch and year specific denominator populations are from the Tricare data base.Age adjustment was calculated using the inverse variance of the observed rates.There is minimal random variation in these estimates.
of Army, Air Force and Navy increases suggest the observed peakfrom 1999–2000 is not likely the result of random variation.
 3.2. Case distribution
The geographic distribution of Fallon cancer cases exhibits anotable but not obvious annulus surrounding the downtown Fal-lonarea(Fig.3A).Tobettervisualizethesedata,adensityequalizedmap(DEMP)projectionwasutilized(Fig.3B)[26].DEMPdistributes areal units based on population density, making the density of thepopulationequalacrossthemap.Ifthedistributionofeventswithina population is random, those events should be evenly distributedat random over a DEMP-generated map.Thelikelihoodthattheseobservedspatialdistributionsarosebychance alone was tested using the test of variance. The residencesoftheleukemiacaseswerecomparedtothe2000U.S.Censuspop-ulation and the residences of all cancer (except leukemia) cases,recordedintheNevadacancerregistryduring1999–2004.Thegoalwas to identify any notable pattern that might suggest a commonexposure.Allnon-leukemiacancersinthe1999–2004periodwereshowntoresideinthesamespatialstructureastheunderlyingpop-ulation(
 p
-value=0.74;testofvariance)(Fig.3A).Yetthelocationof theclustercaseswasfoundtobesignificantlydifferentfromthatof theunderlyingpopulation(
 p
-value<0.01;testofvariance;Fig.4B).Non-leukemia pediatric cancers werealso plotted, and it is clear
Fig. 3.
Geospatial organization of cancer cases and environmental features in Churchill County. Vegetation synthesis map of Churchill County (A) Spatial organization of leukemiacases(redcircles)overtheclustertimeperiod.Locationsareenlargedand“jitteredtomaintainconfidentiality.(B)Density-equalizedmapofthesameinformationas(A),leukemiacases(redcircles).Non-leukemiapediatriccancers(yellowsquare)arealsodisplayed.Onthismap,thespatialstructureisalteredtocreateanequaldistancebetween members of the population. (C) Location of leukemia cases (red circles), non-leukemia cancer cases (green diamonds), and non-leukemia pediatric cancers (yellowsquare) on the DEMP projection. Non-leukemia cancer cases appear randomly distributed. The paucity of cancer cases in the lower right of the graph is due to incompletereporting of cancer to the Nevada registry from the US Navy Air Station. (D) Tested mosquito pools (in the year 2004) are shown by crosses, and those that were negativeand positive for WNV are indicated in blue and yellow, respectively. Leukemia cluster cases are indicated (red circles).

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