Publications by authors named "Ashley H Beecham"

15 Publications

  • Page 1 of 1

Two genetic variants explain the association of European ancestry with multiple sclerosis risk in African-Americans.

Sci Rep 2020 10 9;10(1):16902. Epub 2020 Oct 9.

Department of Genetics, Harvard Medical School, New Research Building, Boston, MA, 02115, USA.

Epidemiological studies have suggested differences in the rate of multiple sclerosis (MS) in individuals of European ancestry compared to African ancestry, motivating genetic scans to identify variants that could contribute to such patterns. In a whole-genome scan in 899 African-American cases and 1155 African-American controls, we confirm that African-Americans who inherit segments of the genome of European ancestry at a chromosome 1 locus are at increased risk for MS [logarithm of odds (LOD) = 9.8], although the signal weakens when adding an additional 406 cases, reflecting heterogeneity in the two sets of cases [logarithm of odds (LOD) = 2.7]. The association in the 899 individuals can be fully explained by two variants previously associated with MS in European ancestry individuals. These variants tag a MS susceptibility haplotype associated with decreased CD58 gene expression (odds ratio of 1.37; frequency of 84% in Europeans and 22% in West Africans for the tagging variant) as well as another haplotype near the FCRL3 gene (odds ratio of 1.07; frequency of 49% in Europeans and 8% in West Africans). Controlling for all other genetic and environmental factors, the two variants predict a 1.44-fold higher rate of MS in European-Americans compared to African-Americans.
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http://dx.doi.org/10.1038/s41598-020-74035-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547691PMC
October 2020

Fine-Mapping Array Design for Multi-Ethnic Studies of Multiple Sclerosis.

Genes (Basel) 2019 11 7;10(11). Epub 2019 Nov 7.

John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.

While approximately 200 autosomal genetic associations outside of the major histocompatibility complex (MHC) have been identified for multiple sclerosis (MS) risk in European populations, causal variants identified at the majority of these associated loci have been much more elusive. We propose that knowledge gained from replication efforts in Hispanic and African American populations can be utilized to more efficiently fine-map these risk loci. To this end, we have customized a genotyping array by adding ~20,000 bead types (~17,000 variants) to the base content of the Ilumina Infinium expanded multi-ethnic genotyping array and the Infinium ImmunoArray-24 v2 BeadChip. These custom bead types were chosen to allow for the detection of causal variation (1) in the presence of allelic and locus heterogeneity, by incorporating regulatory and coding variation within 1-Mb of previously identified risk variants and (2) in the absence of allelic and locus heterogeneity by incorporation of variants using linkage disequilibrium criteria, which are based on knowledge of replication status in Hispanic and African American study samples. This array has been designed to maximize fine-mapping potential for currently identified MS susceptibility loci, particularly in multi-ethnic populations. The strategies described here could be additionally informative for fine-mapping of other disease phenotypes.
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http://dx.doi.org/10.3390/genes10110903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895860PMC
November 2019

The emerging genetic landscape of cerebral white matter hyperintensities.

Neurology 2019 02 18;92(8):355-356. Epub 2019 Jan 18.

From the Institute of Molecular Medicine and Human Genetics Center (M.F.), University of Texas Health Science Center at Houston; and John P. Hussman Institute for Human Genomics (A.H.B.), University of Miami, FL.

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http://dx.doi.org/10.1212/WNL.0000000000006936DOI Listing
February 2019

Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting.

Neurology 2019 Jan 16. Epub 2019 Jan 16.

Objective: To explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts.

Methods: We performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n = 20,949) from 5 ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6,862; 1,483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI.

Results: The mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, = 1.77 × 10; and LINC00539/ZDHHC20, = 5.82 × 10. Both have been associated with blood pressure (BP)-related phenotypes, but did not replicate in the smaller follow-up sample or show associations with related phenotypes. Age- and sex-adjusted associations with BI and SSBI were observed for BP traits ( value for BI, = 9.38 × 10; = 5.23 × 10 for hypertension), smoking ( = 4.4 × 10; = 1.2 × 10), diabetes ( = 1.7 × 10; = 2.8 × 10), previous cardiovascular disease ( = 1.0 × 10; = 2.3 × 10), stroke ( = 3.9 × 10; = 3.2 × 10), and MRI-defined white matter hyperintensity burden ( = 1.43 × 10; = 3.16 × 10), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI ( ≤ 0.0022), without indication of directional pleiotropy.

Conclusion: In this multiethnic GWAS meta-analysis, including over 20,000 population-based participants, we identified genetic risk loci for BI requiring validation once additional large datasets become available. High BP, including genetically determined, was the most significant modifiable, causal risk factor for BI.
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http://dx.doi.org/10.1212/WNL.0000000000006851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369905PMC
January 2019

Native ancestry is associated with optic neuritis and age of onset in hispanics with multiple sclerosis.

Ann Clin Transl Neurol 2018 Nov 23;5(11):1362-1371. Epub 2018 Sep 23.

Dr. John T. Macdonald Department of Human Genetics Miller School of Medicine University of Miami Miami Florida.

Background And Objective: Hispanics with multiple sclerosis (MS) present younger and more often with optic neuritis (ON) as compared to Whites in the western United States. Regional differences related to Hispanic genetic admixture could be responsible. We investigated the association between global genetic ancestry and ON and age at onset of MS in Hispanics.

Methods: Data were obtained for 1033 self-identified Hispanics with MS from four MS-based registries from four academic institutions across the United States January 2016-April 2017. Multivariate regression models, utilizing genetic ancestry estimates for Native American (NA), African, and European ancestry, were used to assess the relationship between genetic ancestry and ON presentation and age of MS onset, defined as age at first symptom.

Results: Genetic ancestry and ON proportions varied by region where NA ancestry and ON proportions were highest among Hispanics in the southwestern United States (40% vs. 19% overall for NA and 38% vs. 25% overall for ON). A strong inverse correlation was observed between NA and European ancestry ( = -0.83). ON presentation was associated with younger age of onset (OR: 0.98; 95% CI: 0.96-0.99; =7.80 × 10) and increased NA ancestry (OR: 2.35 for the highest versus the lowest quartile of NA ancestry; 95% CI: 1.35-4.10;  = 2.60 × 10). Younger age of onset was found to be associated with a higher proportion NA (Beta: -5.58;  = 3.49 × 10) and African ancestry (Beta: -10.07;  = 1.39 × 10).

Interpretation: Ethnic differences associated with genetic admixture could influence clinical presentation in Hispanics with MS; underscoring the importance of considering genetic substructure in future clinical, genetic, and epigenetic studies in Hispanics.
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http://dx.doi.org/10.1002/acn3.646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6243381PMC
November 2018

Properties of global- and local-ancestry adjustments in genetic association tests in admixed populations.

Genet Epidemiol 2018 03 30;42(2):214-229. Epub 2017 Dec 30.

John P. Hussman Institute for Human Genetics, Miller School of Medicine, University of Miami, Miami, Florida, United States of America.

Population substructure can lead to confounding in tests for genetic association, and failure to adjust properly can result in spurious findings. Here we address this issue of confounding by considering the impact of global ancestry (average ancestry across the genome) and local ancestry (ancestry at a specific chromosomal location) on regression parameters and relative power in ancestry-adjusted and -unadjusted models. We examine theoretical expectations under different scenarios for population substructure; applying different regression models, verifying and generalizing using simulations, and exploring the findings in real-world admixed populations. We show that admixture does not lead to confounding when the trait locus is tested directly in a single admixed population. However, if there is more complex population structure or a marker locus in linkage disequilibrium (LD) with the trait locus is tested, both global and local ancestry can be confounders. Additionally, we show the genotype parameters of adjusted and unadjusted models all provide tests for LD between the marker and trait locus, but in different contexts. The local ancestry adjusted model tests for LD in the ancestral populations, while tests using the unadjusted and the global ancestry adjusted models depend on LD in the admixed population(s), which may be enriched due to different ancestral allele frequencies. Practically, this implies that global-ancestry adjustment should be used for screening, but local-ancestry adjustment may better inform fine mapping and provide better effect estimates at trait loci.
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http://dx.doi.org/10.1002/gepi.22103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5811405PMC
March 2018

Novel genetic loci associated with hippocampal volume.

Nat Commun 2017 01 18;8:13624. Epub 2017 Jan 18.

Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808, USA.

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (r=-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.
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http://dx.doi.org/10.1038/ncomms13624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5253632PMC
January 2017

Novel genetic loci underlying human intracranial volume identified through genome-wide association.

Nat Neurosci 2016 12 3;19(12):1569-1582. Epub 2016 Oct 3.

Brain Center Rudolf Magnus, Department of Psychiatry, UMC Utrecht, Utrecht, the Netherlands.

Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five previously unknown loci for intracranial volume and confirmed two known signals. Four of the loci were also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (ρ = 0.748), which indicates a similar genetic background and allowed us to identify four additional loci through meta-analysis (N = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, and Parkinson's disease, and were enriched near genes involved in growth pathways, including PI3K-AKT signaling. These findings identify the biological underpinnings of intracranial volume and their link to physiological and pathological traits.
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http://dx.doi.org/10.1038/nn.4398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5227112PMC
December 2016

Class II HLA interactions modulate genetic risk for multiple sclerosis.

Nat Genet 2015 Oct 7;47(10):1107-1113. Epub 2015 Sep 7.

Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.

Association studies have greatly refined the understanding of how variation within the human leukocyte antigen (HLA) genes influences risk of multiple sclerosis. However, the extent to which major effects are modulated by interactions is poorly characterized. We analyzed high-density SNP data on 17,465 cases and 30,385 controls from 11 cohorts of European ancestry, in combination with imputation of classical HLA alleles, to build a high-resolution map of HLA genetic risk and assess the evidence for interactions involving classical HLA alleles. Among new and previously identified class II risk alleles (HLA-DRB1*15:01, HLA-DRB1*13:03, HLA-DRB1*03:01, HLA-DRB1*08:01 and HLA-DQB1*03:02) and class I protective alleles (HLA-A*02:01, HLA-B*44:02, HLA-B*38:01 and HLA-B*55:01), we find evidence for two interactions involving pairs of class II alleles: HLA-DQA1*01:01-HLA-DRB1*15:01 and HLA-DQB1*03:01-HLA-DQB1*03:02. We find no evidence for interactions between classical HLA alleles and non-HLA risk-associated variants and estimate a minimal effect of polygenic epistasis in modulating major risk alleles.
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http://dx.doi.org/10.1038/ng.3395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4874245PMC
October 2015

Clinical Expression of Multiple Sclerosis in Hispanic Whites of Primarily Caribbean Ancestry.

Neuroepidemiology 2015 11;44(4):262-8. Epub 2015 Jul 11.

John P. Hussman Institute for Human Genomics, University of Miami, Miami, Fla., USA.

Objective: The clinical characteristics of multiple sclerosis (MS) are not well defined in Hispanic populations. We hypothesized that disease presentation in Hispanic white (HW) patients will be different from non-Hispanic white (NHW) patients given their ancestral background and reported lower disease prevalence. This study was undertaken to compare HW of primarily Caribbean ancestry to NHW on clinical characteristics of MS.

Methods: We assessed 312 HW and 312 NHW patients with definite MS for clinical disease characteristics obtained through consented review of medical records. In order to assess the relationship between age-related phenotypes and ethnicity, linear regression was used. Logistic regression was used to assess the relationship between ethnicity and descriptors of disease presentation and severity as well as presence of neurological symptoms.

Results: We observed a significantly younger age at diagnosis (p = 1.38E-02) and age at exam (p = 2.36E-05) in HW. However, age at first symptom did not differ significantly between the two groups. Furthermore, within HW, the mean age at first symptom and age at diagnosis was significantly younger in those born in the United States (p < 1.00E-03 for both). Interestingly, we noted an increase in ambulatory disability in HW patients, primarily among those with relapsing disease (p = 4.18E-03).

Conclusions: We found several differences in age-related phenotypes and disease severity between HW of primarily Caribbean origin and NHW patients. To our knowledge, this is the largest study to date that examined the clinical characteristics of MS in Hispanic patients of largely Caribbean origin.
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http://dx.doi.org/10.1159/000431375DOI Listing
April 2016

An ImmunoChip study of multiple sclerosis risk in African Americans.

Brain 2015 Jun 28;138(Pt 6):1518-30. Epub 2015 Mar 28.

1 Department of Neurology, School of Medicine, University of California, San Francisco, CA 94158, USA

The aims of this study were: (i) to determine to what degree multiple sclerosis-associated loci discovered in European populations also influence susceptibility in African Americans; (ii) to assess the extent to which the unique linkage disequilibrium patterns in African Americans can contribute to localizing the functionally relevant regions or genes; and (iii) to search for novel African American multiple sclerosis-associated loci. Using the ImmunoChip custom array we genotyped 803 African American cases with multiple sclerosis and 1516 African American control subjects at 130 135 autosomal single nucleotide polymorphisms. We conducted association analysis with rigorous adjustments for population stratification and admixture. Of the 110 non-major histocompatibility complex multiple sclerosis-associated variants identified in Europeans, 96 passed stringent quality control in our African American data set and of these, >70% (69) showed over-representation of the same allele amongst cases, including 21 with nominally significant evidence for association (one-tailed test P < 0.05). At a further eight loci we found nominally significant association with an alternate correlated risk-tagging single nucleotide polymorphism from the same region. Outside the regions known to be associated in Europeans, we found seven potentially associated novel candidate multiple sclerosis variants (P < 10(-4)), one of which (rs2702180) also showed nominally significant evidence for association (one-tailed test P = 0.034) in an independent second cohort of 620 African American cases and 1565 control subjects. However, none of these novel associations reached genome-wide significance (combined P = 6.3 × 10(-5)). Our data demonstrate substantial overlap between African American and European multiple sclerosis variants, indicating common genetic contributions to multiple sclerosis risk.
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http://dx.doi.org/10.1093/brain/awv078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4553906PMC
June 2015

Multiethnic genome-wide association study of cerebral white matter hyperintensities on MRI.

Circ Cardiovasc Genet 2015 Apr 7;8(2):398-409. Epub 2015 Feb 7.

Background: The burden of cerebral white matter hyperintensities (WMH) is associated with an increased risk of stroke, dementia, and death. WMH are highly heritable, but their genetic underpinnings are incompletely characterized. To identify novel genetic variants influencing WMH burden, we conducted a meta-analysis of multiethnic genome-wide association studies.

Methods And Results: We included 21 079 middle-aged to elderly individuals from 29 population-based cohorts, who were free of dementia and stroke and were of European (n=17 936), African (n=1943), Hispanic (n=795), and Asian (n=405) descent. WMH burden was quantified on MRI either by a validated automated segmentation method or a validated visual grading scale. Genotype data in each study were imputed to the 1000 Genomes reference. Within each ethnic group, we investigated the relationship between each single-nucleotide polymorphism and WMH burden using a linear regression model adjusted for age, sex, intracranial volume, and principal components of ancestry. A meta-analysis was conducted for each ethnicity separately and for the combined sample. In the European descent samples, we confirmed a previously known locus on chr17q25 (P=2.7×10(-19)) and identified novel loci on chr10q24 (P=1.6×10(-9)) and chr2p21 (P=4.4×10(-8)). In the multiethnic meta-analysis, we identified 2 additional loci, on chr1q22 (P=2.0×10(-8)) and chr2p16 (P=1.5×10(-8)). The novel loci contained genes that have been implicated in Alzheimer disease (chr2p21 and chr10q24), intracerebral hemorrhage (chr1q22), neuroinflammatory diseases (chr2p21), and glioma (chr10q24 and chr2p16).

Conclusions: We identified 4 novel genetic loci that implicate inflammatory and glial proliferative pathways in the development of WMH in addition to previously proposed ischemic mechanisms.
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http://dx.doi.org/10.1161/CIRCGENETICS.114.000858DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4427240PMC
April 2015

Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis.

Nat Genet 2013 Nov 29;45(11):1353-60. Epub 2013 Sep 29.

1] John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, Florida, USA. [2].

Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.
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http://dx.doi.org/10.1038/ng.2770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3832895PMC
November 2013

Interrogating the complex role of chromosome 16p13.13 in multiple sclerosis susceptibility: independent genetic signals in the CIITA-CLEC16A-SOCS1 gene complex.

Hum Mol Genet 2011 Sep 8;20(17):3517-24. Epub 2011 Jun 8.

Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, TN 37232-0700, USA.

Multiple sclerosis (MS) is a neurodegenerative, autoimmune disease of the central nervous system, and numerous studies have shown that MS has a strong genetic component. Independent studies to identify MS-associated genes have often indicated multiple signals in physically close genomic regions, although by their proximity it is not always clear if these data indicate redundant or truly independent genetic signals. Recently, three MS study samples were genotyped in parallel using an Illumina Custom BeadChip. These revealed multiple significantly associated single-nucleotide polymorphisms within a 600 kb stretch on chromosome 16p13. Here we present a detailed analysis of variants in this region that clarifies the independent nature of these signals. The linkage disequilibrium patterns in the region and logistic regression analysis of the associations suggest that this region likely harbors three independent MS disease loci. Further, we examined cis-expression QTLs, histone modifications and CCCTC-binding factor (CTCF) binding data in the region. We also tested for correlated expression of the genes from the region using whole-genome expression array data from lymphoblastoid cell lines. Three of the genes show expression correlations across loci. Furthermore, in the GM12878 lymphoblastoid cell line, these three genes are in a continuous region devoid of H3K27 methylation, suggesting an open chromatin configuration. This region likely only contributes minimal risk to MS; however, investigation of this region will undoubtedly provide insight into the functional mechanisms of these genes. These data highlight the importance of taking a closer look at the expression and function of chromosome 16p13 in the pathogenesis of MS.
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http://dx.doi.org/10.1093/hmg/ddr250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3153306PMC
September 2011

Factors associated with failed retrieval of the Günther Tulip inferior vena cava filter.

J Vasc Interv Radiol 2008 Sep 21;19(9):1321-7. Epub 2008 Jul 21.

Department of Radiology, University of North Carolina, Chapel Hill, North Carolina 27599-7510, USA.

Purpose: To identify potential factors associated with failed retrieval of the Günther Tulip inferior vena cava (IVC) filter.

Materials And Methods: A retrospective review was performed of patients who underwent placement of the Günther Tulip filter with at least one attempt at filter retrieval over a 3-year period. Patient demographics, filter dwell time, filter angulation, and filter leg protrusion were analyzed.

Results: A total of 188 patients were included in the study. Primary retrieval success was achieved in 166 patients (88.3%), for an overall retrieval success rate of 94.2%. The overall mean dwell time was 63 days, whereas the mean dwell time in cases of retrieval failure was 95.4 days. A total of seven filters were in place for longer than 6 months, four of which were successfully retrieved. The degree of filter tilt was not found to be significantly related to retrieval success (P = .36), even though filter angulation was commonly cited as a reason for retrieval failure. On venography, 90.9% of filters that could not be retrieved showed leg protrusion beyond the lumen of the IVC. Finally, increasing patient age also correlated with retrieval failure (P = .01).

Conclusions: Prolonged dwell time and increasing patient age are associated with failed filter retrieval. However, even filters in place for extended periods can be safely removed.
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http://dx.doi.org/10.1016/j.jvir.2008.06.004DOI Listing
September 2008
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