Sharon A. Chung

STOP questionnaire: a tool to screen patients for obstructive sleep apnea.

Background:Obstructive sleep apnea (OSA) is a major risk factor for perioperative adverse events. However, no screening tool for OSA has been validated in surgical patients. This study was conducted to develop and validate a concise and easy-to-use questionnaire for OSA screening in surgical patients. Methods:After hospital ethics approval, preoperative patients aged 18 yr or older and without previously diagnosed OSA were recruited. After a factor analysis, reliability check, and pilot study; four yes/no questions were used to develop this screening tool. The four questions were respectively related to snoring, tiredness during daytime, observed apnea, and high blood pressure (STOP). For validation, the score from the STOP questionnaire was evaluated versus the apnea–hypopnea index from monitored polysomnography. Results:The STOP questionnaire was given to 2,467 patients, 27.5% classified as being at high risk of OSA. Two hundred eleven patients underwent polysomnography, 34 for the pilot test and 177 for validation. In the validation group, the apnea–hypopnea index was 20 ± 6. The sensitivities of the STOP questionnaire with apnea–hypopnea index greater than 5, greater than 15, and greater than 30 as cutoffs were 65.6, 74.3, and 79.5%, respectively. When incorporating body mass index, age, neck circumference, and gender into the STOP questionnaire, sensitivities were increased to 83.6, 92.9, and 100% with the same apnea–hypopnea index cutoffs. Conclusions:The STOP questionnaire is a concise and easy-to-use screening tool for OSA. It has been developed and validated in surgical patients at preoperative clinics. Combined with body mass index, age, neck size, and gender, it had a high sensitivity, especially for patients with moderate to severe OSA.

Association of Systemic Lupus Erythematosus with C8orf13–BLK and ITGAM–ITGAX

BACKGROUND Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease in which the risk of disease is influenced by complex genetic and environmental contributions. Alleles of HLA-DRB1, IRF5, and STAT4 are established susceptibility genes; there is strong evidence for the existence of additional risk loci. METHODS We genotyped more than 500,000 single-nucleotide polymorphisms (SNPs) in DNA samples from 1311 case subjects with SLE and 1783 control subjects; all subjects were North Americans of European descent. Genotypes from 1557 additional control subjects were obtained from public data repositories. We measured the association between the SNPs and SLE after applying strict quality-control filters to reduce technical artifacts and to correct for the presence of population stratification. Replication of the top loci was performed in 793 case subjects and 857 control subjects from Sweden. RESULTS Genetic variation in the region upstream from the transcription initiation site of the gene encoding B lymphoid tyrosine kinase (BLK) and C8orf13 (chromosome 8p23.1) was associated with disease risk in both the U.S. and Swedish case-control series (rs13277113; odds ratio, 1.39; P=1x10(-10)) and also with altered levels of messenger RNA in B-cell lines. In addition, variants on chromosome 16p11.22, near the genes encoding integrin alpha M (ITGAM, or CD11b) and integrin alpha X (ITGAX), were associated with SLE in the combined sample (rs11574637; odds ratio, 1.33; P=3x10(-11)). CONCLUSIONS We identified and then confirmed through replication two new genetic loci for SLE: a promoter-region allele associated with reduced expression of BLK and increased expression of C8orf13 and variants in the ITGAM-ITGAX region.

A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus

Genome-wide association studies have recently identified at least 15 susceptibility loci for systemic lupus erythematosus (SLE). To confirm additional risk loci, we selected SNPs from 2,466 regions that showed nominal evidence of association to SLE (P < 0.05) in a genome-wide study and genotyped them in an independent sample of 1,963 cases and 4,329 controls. This replication effort identified five new SLE susceptibility loci (P < 5 × 10−8): TNIP1 (odds ratio (OR) = 1.27), PRDM1 (OR = 1.20), JAZF1 (OR = 1.20), UHRF1BP1 (OR = 1.17) and IL10 (OR = 1.19). We identified 21 additional candidate loci with P≤ 1 × 10−5. A candidate screen of alleles previously associated with other autoimmune diseases suggested five loci (P < 1 × 10−3) that may contribute to SLE: IFIH1, CFB, CLEC16A, IL12B and SH2B3. These results expand the number of confirmed and candidate SLE susceptibility loci and implicate several key immunologic pathways in SLE pathogenesis.

Validation of the Berlin Questionnaire and American Society of Anesthesiologists Checklist as Screening Tools for Obstructive Sleep Apnea in Surgical Patients

Background:Because of the high prevalence of obstructive sleep apnea (OSA) and its adverse impact on perioperative outcome, a practical screening tool for surgical patients is required. This study was conducted to validate the Berlin questionnaire and the American Society of Anesthesiologists (ASA) checklist in surgical patients and to compare them with the STOP questionnaire. Methods:After hospital ethics approval, preoperative patients aged 18 yr or older and without previously diagnosed OSA were recruited. The scores from the Berlin questionnaire, ASA checklist, and STOP questionnaire were evaluated versus the apnea–hypopnea index from in-laboratory polysomnography. The perioperative data were collected through chart review. Results:Of 2,467 screened patients, 33, 27, and 28% were respectively classified as being at high risk of OSA by the Berlin questionnaire, ASA checklist, and STOP questionnaire. The performance of the screening tools was evaluated in 177 patients who underwent polysomnography. The sensitivities of the Berlin questionnaire, ASA checklist, and STOP questionnaire were 68.9–87.2, 72.1–87.2, and 65.6–79.5% at different apnea–hypopnea index cutoffs. There was no significant difference between the three screening tools in the predictive parameters. The patients with an apnea–hypopnea index greater than 5 and the patients identified as being at high risk of OSA by the STOP questionnaire or ASA checklist had a significantly increased incidence of postoperative complications. Conclusions:Similar to the STOP questionnaire, the Berlin questionnaire and ASA checklist demonstrated a moderately high level of sensitivity for OSA screening. The STOP questionnaire and the ASA checklist were able to identify the patients who were likely to develop postoperative complications.

A Systemic Review of Obstructive Sleep Apnea and Its Implications for Anesthesiologists

BACKGROUND: Obstructive sleep apnea (OSA) is present in a significant proportion of the population, but the majority of patients remain undiagnosed. It is crucial that anesthesiologists and surgeons recognize the increased perioperative risks associated with undiagnosed OSA. We present a systematic review of the literature on the perioperative management of surgical patients with OSA. METHODS: The scope of this review is restricted to publications in all surgical specialties and in the adult patient population. The main search key words were: “perioperative care,” “sleep apnea,” “obstructive sleep apnea,” “perioperative risk,” and “perioperative care.” The databases Medline, Embase, Biological Abstract, Science Citation Index, and Healthstar were searched for relevant English language articles from 1966 to March 2007. RESULTS: The literature supports an increased perioperative risk in OSA patients. The American Society of Anesthesiologists guidelines support the routine screening for OSA during preoperative assessment, and methods of OSA screening are discussed in this review. This review suggests a number of perioperative management strategies to reduce surgical risk in patients with OSA. However, apart from the consensus-based American Society of Anesthesiologists guidelines, it is important to note that evidence-based recommendations are lacking in the literature. CONCLUSIONS: This review suggests ways to screen for OSA in the preoperative setting and proposes perioperative management strategies. The ultimate goal is to reduce the perioperative risk of OSA patients but, to realize that goal, research will be needed to determine whether screening for OSA and/or adapting specific perioperative management approaches translates into a lessening of adverse events in surgical patients with undiagnosed OSA.

Specificity of the STAT4 Genetic Association for Severe Disease Manifestations of Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a genetically complex disease with heterogeneous clinical manifestations. A polymorphism in the STAT4 gene has recently been established as a risk factor for SLE, but the relationship with specific SLE subphenotypes has not been studied. We studied 137 SNPs in the STAT4 region genotyped in 4 independent SLE case series (total n = 1398) and 2560 healthy controls, along with clinical data for the cases. Using conditional testing, we confirmed the most significant STAT4 haplotype for SLE risk. We then studied a SNP marking this haplotype for association with specific SLE subphenotypes, including autoantibody production, nephritis, arthritis, mucocutaneous manifestations, and age at diagnosis. To prevent possible type-I errors from population stratification, we reanalyzed the data using a subset of subjects determined to be most homogeneous based on principal components analysis of genome-wide data. We confirmed that four SNPs in very high LD (r(2) = 0.94 to 0.99) were most strongly associated with SLE, and there was no compelling evidence for additional SLE risk loci in the STAT4 region. SNP rs7574865 marking this haplotype had a minor allele frequency (MAF) = 31.1% in SLE cases compared with 22.5% in controls (OR = 1.56, p = 10(-16)). This SNP was more strongly associated with SLE characterized by double-stranded DNA autoantibodies (MAF = 35.1%, OR = 1.86, p<10(-19)), nephritis (MAF = 34.3%, OR = 1.80, p<10(-11)), and age at diagnosis<30 years (MAF = 33.8%, OR = 1.77, p<10(-13)). An association with severe nephritis was even more striking (MAF = 39.2%, OR = 2.35, p<10(-4) in the homogeneous subset of subjects). In contrast, STAT4 was less strongly associated with oral ulcers, a manifestation associated with milder disease. We conclude that this common polymorphism of STAT4 contributes to the phenotypic heterogeneity of SLE, predisposing specifically to more severe disease.

Differential Genetic Associations for Systemic Lupus Erythematosus Based on Anti–dsDNA Autoantibody Production

Systemic lupus erythematosus (SLE) is a clinically heterogeneous, systemic autoimmune disease characterized by autoantibody formation. Previously published genome-wide association studies (GWAS) have investigated SLE as a single phenotype. Therefore, we conducted a GWAS to identify genetic factors associated with anti–dsDNA autoantibody production, a SLE–related autoantibody with diagnostic and clinical importance. Using two independent datasets, over 400,000 single nucleotide polymorphisms (SNPs) were studied in a total of 1,717 SLE cases and 4,813 healthy controls. Anti–dsDNA autoantibody positive (anti–dsDNA +, n = 811) and anti–dsDNA autoantibody negative (anti–dsDNA –, n = 906) SLE cases were compared to healthy controls and to each other to identify SNPs associated specifically with these SLE subtypes. SNPs in the previously identified SLE susceptibility loci STAT4, IRF5, ITGAM, and the major histocompatibility complex were strongly associated with anti–dsDNA + SLE. Far fewer and weaker associations were observed for anti–dsDNA – SLE. For example, rs7574865 in STAT4 had an OR for anti–dsDNA + SLE of 1.77 (95% CI 1.57–1.99, p = 2.0E-20) compared to an OR for anti–dsDNA – SLE of 1.26 (95% CI 1.12–1.41, p = 2.4E-04), with pheterogeneity<0.0005. SNPs in the SLE susceptibility loci BANK1, KIAA1542, and UBE2L3 showed evidence of association with anti–dsDNA + SLE and were not associated with anti–dsDNA – SLE. In conclusion, we identified differential genetic associations with SLE based on anti–dsDNA autoantibody production. Many previously identified SLE susceptibility loci may confer disease risk through their role in autoantibody production and be more accurately described as autoantibody propensity loci. Lack of strong SNP associations may suggest that other types of genetic variation or non-genetic factors such as environmental exposures have a greater impact on susceptibility to anti–dsDNA – SLE.

The Berlin questionnaire for sleep apnea in a sleep clinic population: relationship to polysomnographic measurement of respiratory disturbance

The Berlin questionnaire (BQ) has been used to help identify patients at high risk of having sleep apnea in primary care and atrial fibrillation patients. The BQ may be a useful adjunct in sleep medicine and research, but it has never been validated in a sleep clinic population. The aim of the study is to determine the specificity and sensitivity of the BQ compared to the respiratory disturbance index (RDI) values obtained from two nights of polysomnographic recording in a sleep clinic population. This is a retrospective chart review study of 130 sleep clinic patients. Patients’ demographics, BQ scores, RDI measurements, and sleep study parameters were extracted from the patients’ chart. Of the 130 charts reviewed, the BQ identified 76 (58.5%) as being at high-risk of having sleep apnea, but overnight polysomnography found only 34 of the 130 patients (26.2%) had an RDI > 10. The BQ performed with 0.62 sensitivity and 0.43 specificity at the RDI > 10 level. Due to the low sensitivity and specificity as well as the large number of false negatives and positives, the Berlin questionnaire is not an appropriate instrument for identifying patients with sleep apnea in a sleep clinic population.

Risk Alleles for Systemic Lupus Erythematosus in a Large Case-Control Collection and Associations with Clinical Subphenotypes

Systemic lupus erythematosus (SLE) is a genetically complex disease with heterogeneous clinical manifestations. Recent studies have greatly expanded the number of established SLE risk alleles, but the distribution of multiple risk alleles in cases versus controls and their relationship to subphenotypes have not been studied. We studied 22 SLE susceptibility polymorphisms with previous genome-wide evidence of association (p<5×10−8) in 1919 SLE cases from 9 independent Caucasian SLE case series and 4813 independent controls. The mean number of risk alleles in cases was 15.1 (SD 3.1) while the mean in controls was 13.1 (SD 2.8), with trend p = 4×10−128. We defined a genetic risk score (GRS) for SLE as the number of risk alleles with each weighted by the SLE risk odds ratio (OR). The OR for high-low GRS tertiles, adjusted for intra-European ancestry, sex, and parent study, was 4.4 (95% CI 3.8–5.1). We studied associations of individual SNPs and the GRS with clinical manifestations for the cases: age at diagnosis, the 11 American College of Rheumatology classification criteria, and double-stranded DNA antibody (anti-dsDNA) production. Six subphenotypes were significantly associated with the GRS, most notably anti-dsDNA (ORhigh-low = 2.36, p = 9e−9), the immunologic criterion (ORhigh-low = 2.23, p = 3e−7), and age at diagnosis (ORhigh-low = 1.45, p = 0.0060). Finally, we developed a subphenotype-specific GRS (sub-GRS) for each phenotype with more power to detect cumulative genetic associations. The sub-GRS was more strongly associated than any single SNP effect for 5 subphenotypes (the above plus hematologic disorder and oral ulcers), while single loci are more significantly associated with renal disease (HLA-DRB1, OR = 1.37, 95% CI 1.14–1.64) and arthritis (ITGAM, OR = 0.72, 95% CI 0.59–0.88). We did not observe significant associations for other subphenotypes, for individual loci or the sub-GRS. Thus our analysis categorizes SLE subphenotypes into three groups: those having cumulative, single, and no known genetic association with respect to the currently established SLE risk loci.

A comprehensive analysis of shared loci between systemic lupus erythematosus (SLE) and sixteen autoimmune diseases reveals limited genetic overlap

In spite of the well-known clustering of multiple autoimmune disorders in families, analyses of specific shared genes and polymorphisms between systemic lupus erythematosus (SLE) and other autoimmune diseases (ADs) have been limited. Therefore, we comprehensively tested autoimmune variants for association with SLE, aiming to identify pleiotropic genetic associations between these diseases. We compiled a list of 446 non–Major Histocompatibility Complex (MHC) variants identified in genome-wide association studies (GWAS) of populations of European ancestry across 17 ADs. We then tested these variants in our combined Caucasian SLE cohorts of 1,500 cases and 5,706 controls. We tested a subset of these polymorphisms in an independent Caucasian replication cohort of 2,085 SLE cases and 2,854 controls, allowing the computation of a meta-analysis between all cohorts. We have uncovered novel shared SLE loci that passed multiple comparisons adjustment, including the VTCN1 (rs12046117, P = 2.02×10−06) region. We observed that the loci shared among the most ADs include IL23R, OLIG3/TNFAIP3, and IL2RA. Given the lack of a universal autoimmune risk locus outside of the MHC and variable specificities for different diseases, our data suggests partial pleiotropy among ADs. Hierarchical clustering of ADs suggested that the most genetically related ADs appear to be type 1 diabetes with rheumatoid arthritis and Crohns disease with ulcerative colitis. These findings support a relatively distinct genetic susceptibility for SLE. For many of the shared GWAS autoimmune loci, we found no evidence for association with SLE, including IL23R. Also, several established SLE loci are apparently not associated with other ADs, including the ITGAM-ITGAX and TNFSF4 regions. This study represents the most comprehensive evaluation of shared autoimmune loci to date, supports a relatively distinct non–MHC genetic susceptibility for SLE, provides further evidence for previously and newly identified shared genes in SLE, and highlights the value of studies of potentially pleiotropic genes in autoimmune diseases.