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1.  American College of Rheumatology Classification Criteria for Sjögren’s Syndrome: A Data-Driven, Expert Consensus Approach in the SICCA Cohort 
Arthritis care & research  2012;64(4):475-487.
Objectives
We propose new classification criteria for Sjögren’s Syndrome (SS), which are needed considering the emergence of biological agents as potential treatments and their associated co-morbidity. These criteria target individuals with signs/symptoms suggestive of SS.
Methods
Criteria are based on expert opinion elicited using the Nominal Group Technique, and analyses of data from the Sjögren’s International Collaborative Clinical Alliance. Preliminary criteria validation included comparisons with classifications based on the American-European-Consensus-Group (AECG) criteria, a model-based “gold standard” obtained from Latent Class Analysis (LCA) of data from a range of diagnostic tests, and a comparison with cases and controls collected from sources external to the population used for criteria development
Results
Validation results indicate high levels of sensitivity and specificity for the criteria. Case definition requires at least 2 out of the following 3:
Positive serum anti-SSA and/or anti-SSB or [positive rheumatoid factor and ANA ≥ 1:320];
Ocular staining score ≥ 3;
Presence of focal lymphocytic sialadenitis with focus score ≥ 1 focus/4mm2 in labial salivary gland biopsies.
Observed agreement with the AECG criteria is high when these are applied using all objective tests. However, AECG classification based on allowable substitutions of symptoms for objective tests results in poor agreement with the proposed and LCA-derived classifications.
Conclusion
These classification criteria developed from registry data collected using standardized measures are based on objective tests. Validation indicates improved classification performance relative to existing alternatives, making them more suitable for application in situations where misclassification may present health risks.
PMCID: PMC3349440  PMID: 22563590
3.  Supervised machine learning and logistic regression identifies novel epistatic risk factors with PTPN22 for rheumatoid arthritis 
Genes and immunity  2010;11(3):199-208.
Investigating genetic interactions (epistasis) has proven difficult despite the recent advances of both laboratory methods and statistical developments. With no ‘best’ statistical approach available, combining several analytical methods may be optimal for detecting epistatic interactions. Using a multi-stage analysis that incorporated supervised machine learning and methods of association testing, we investigated epistatic interactions with a well-established genetic factor (PTPN22 1858T) in a complex autoimmune disease (rheumatoid arthritis (RA)). Our analysis consisted of four principal stages: Stage I (data reduction)—identifying candidate chromosomal regions in 292 affected sibling pairs, by predicting PTPN22 concordance using multipoint identity-by-descent probabilities and a supervised machine learning algorithm (Random Forests); Stage II (extension analysis)—testing detailed genetic data within candidate chromosomal regions for epistasis with PTPN22 1858T in 677 cases and 750 controls using logistic regression; Stage III (replication analysis)—confirmation of epistatic interactions in 947 cases and 1756 controls; Stage IV (combined analysis)—a pooled analysis including all 1624 RA cases and 2506 control subjects for final estimates of effect size. A total of seven replicating epistatic interactions were identified. SNP variants within CDH13, MYO3A, CEP72 and near WFDC1 showed significant evidence for interaction with PTPN22, affecting susceptibility to RA.
doi:10.1038/gene.2009.110
PMCID: PMC3118040  PMID: 20090771
epistasis; rheumatoid arthritis; PTPN22; Random Forests
4.  A candidate gene study of CLEC16A does not provide evidence of association with risk for anti-CCP-positive rheumatoid arthritis 
Genes and immunity  2010;11(6):504-508.
CLEC16A, a putative immunoreceptor, was recently established as a susceptibility locus for type I diabetes and multiple sclerosis. Subsequently, associations between CLEC16A and rheumatoid arthritis (RA), Addison’s disease and Crohn’s disease have been reported. A large comprehensive and independent investigation of CLEC16A variation in RA was pursued. This study tested 251 CLEC16A single-nucleotide polymorphisms in 2542 RA cases (85% anti-cyclic citrullinated peptide (anti-CCP) positive) and 2210 controls (N = 4752). All individuals were of European ancestry, as determined by ancestry informative genetic markers. No evidence for significant association between CLEC16A variation and RA was observed. This is the first study to fully characterize common genetic variation in CLEC16A including assessment of haplotypes and gender-specific effects. The previously reported association between RA and rs6498169 was not replicated. Results show that CLEC16A does not have a prominent function in susceptibility to anti-CCP-positive RA.
doi:10.1038/gene.2010.7
PMCID: PMC2992879  PMID: 20220768
rheumatoid arthritis; anti-CCP antibodies; autoimmunity; CLEC16A; KIAA0350
5.  Association of PDCD1 genetic variation with risk and clinical manifestations of systemic lupus erythematosus in a multiethnic cohort 
Genes and immunity  2007;8(4):279-287.
We evaluated the roles of five single-nucleotide polymorphisms (SNPs) within PDCD1, and haplotypes defined by these SNPs, for the development of systemic lupus erythematosus (SLE) and specific sub-phenotypes (nephritis, antiphospholipid antibody positive, arthritis and double-stranded DNA positive) within a multiethnic US cohort of 1036 patients. Family based analyses were performed using 844 simplex families from four ethnic groups (Caucasian, Asian, Hispanic and African American). Subjects were genotyped for five ‘tag’ SNPs (selected from 15) to provide complete genetic information in all main ethnic groups. We employed transmission disequilibrium testing to assess risk for SLE by allele or haplotype, and multiple logistic regression analysis of SLE cases to examine associations with specific sub-phenotypes. In family based analyses, a haplotype containing the PD1.3A allele was significantly associated with SLE susceptibility among Caucasian families (P = 0.01). Among Hispanic families, two novel SNPs were associated with SLE risk (P = 0.005 and 0.01). In multivariate logistic regression analyses, five haplotypes were associated with specific sub-phenotypes among the different ethnic groups. These results suggest that PDCD1 genetic variation influences the risk and expression of SLE and that these associations vary according to ethnic background.
doi:10.1038/sj.gene.6364383
PMCID: PMC2925679  PMID: 17344889
systemic lupus erythematosus; PDCD1; family-based methods; haplotypes
6.  Factor V Leiden and Thrombosis in Patients with Systemic Lupus Erythematosus (SLE): A Meta-analysis 
Genes and immunity  2009;10(5):495-502.
To perform a meta-analysis of the association between the factor V Leiden polymorphism (FVL) and thrombosis among patients with SLE and/or antiphospholipid antibody (aPL) positivity. Included studies recruited patients based on SLE or aPL positive status, confirmed subjects' SLE diagnosis as defined by the American College of Rheumatology, and documented thrombotic events. Excluded studies were non-English or considered only arterial thrombosis. Individual patient data, available from five studies, together with unpublished data from 1210 European-American SLE patients from the UCSF Lupus Genetics Collection genotyped for FVL, were further analyzed. Seventeen studies (n=2090 subjects) were included in the initial meta-analysis. Unadjusted odds ratios (OR) were calculated to assess association of FVL with thrombosis. The OR for association of thrombosis with FVL was 2.88 (95% C.I. 1.98-4.20). In the secondary analysis with our individual patient dataset (n=1447 European-derived individuals), SLE subjects with the FVL polymorphism still had more than two times the odds of thrombosis compared to subjects without this polymorphism, even when adjusting for covariates such as gender, age, and aPL status. SLE and/or aPL positive patients with the FVL variant have more than two times the odds of thrombosis compared to those without this polymorphism.
doi:10.1038/gene.2009.32
PMCID: PMC2766554  PMID: 19421222
Systemic lupus erythematosus; factor V Leiden polymorphism; thrombosis; risk factors; antiphospholipid antibodies
7.  Time to lupus nephritis: impact of gender and ethnicity 
Arthritis Research  2001;3(Suppl A):P110.
doi:10.1186/ar279
PMCID: PMC3273253

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