Carin Y. Smith

Usefulness of Red Cell Distribution Width to Predict Mortality in Patients With Peripheral Artery Disease

Increased red blood cell distribution width (RDW), a marker of anisocytosis, has been associated with adverse outcomes in multiple settings. Whether RDW is predictive of mortality in patients with peripheral artery disease (PAD) is unknown. We studied 13,039 consecutive outpatients (69.5 ± 12.0 years of age, 60.9% men, 97.6% white) with PAD identified by noninvasive lower-extremity arterial testing at the Mayo Clinic from January 1997 through December 2007, with follow-up through September 2009. We defined PAD as a low (≤ 0.9) or high (≥ 1.4) ankle-brachial index (ABI). Cardiovascular risk factors and co-morbidities were ascertained using electronic medical record-based algorithms. RDW was obtained from the complete blood cell count drawn around the time of arterial evaluation. Mortality was ascertained using the Mayo electronic medical record and Accurint databases. Association of RDW with all-cause mortality was analyzed by multivariable Cox proportional hazards regression. During a median follow-up of 5.5 years, 4,039 (31.0%) deaths occurred (28.7% in low and 38.9% in high ABI subsets). After adjustment for age, gender, cardiovascular risk factors, and co-morbidities, patients in the highest quartile of RDW (> 14.5%) had a 66% greater risk of mortality compared to the lowest quartile (< 12.8%, p < 0.0001); a 1% increment in RDW was associated with a 10% greater risk of all-cause mortality (hazard ratio 1.10, 95% confidence interval 1.08 to 1.12, p < 0.0001). The adjusted hazard ratio was similar in the low (1.10, 1.08 to 1.12) and high (1.09, 1.06 to 1.12) ABI subsets. In conclusion, RDW, a routinely available measurement, is an independent prognostic marker in patients with PAD.

Updated estimate of AQP4-IgG serostatus and disability outcome in neuromyelitis optica

Objective: To 1) determine, using contemporary recombinant antigen–based assays, the aquaporin-4 (AQP4)–immunoglobulin G (IgG) detection rate in sequential sera of patients assigned a clinical diagnosis of neuromyelitis optica (NMO) but initially scored negative by tissue-based indirect immunofluorescence (IIF) assay; and 2) evaluate the impact of serostatus on phenotype and outcome. Methods: From Mayo Clinic records (2005–2011), we identified 163 patients with NMO; 110 (67%) were seropositive by IIF and 53 (33%) were scored seronegative. Available stored sera from 49 “seronegative” patients were tested by ELISA, AQP4-transfected cell-based assay, and in-house fluorescence-activated cell sorting assay. Clinical characteristics were compared based on final serostatus. Results: Thirty of the 49 IIF-negative patients (61%) were reclassified as seropositive, yielding an overall AQP4-IgG seropositivity rate of 88% (i.e., 12% seronegative). The fluorescence-activated cell sorting assay improved the detection rate to 87%, cell-based assay to 84%, and ELISA to 79%. The sex ratio (female to male) was 1:1 for seronegatives and 9:1 for seropositives (p < 0.0001). Simultaneous optic neuritis and transverse myelitis as onset attack type (i.e., within 30 days of each other) occurred in 32% of seronegatives and in 3.6% of seropositives (p < 0.0001). Relapse rate, disability outcome, and other clinical characteristics did not differ significantly. Conclusions: Serological tests using recombinant AQP4 antigen are significantly more sensitive than tissue-based IIF for detecting AQP4-IgG. Testing should precede immunotherapy; if negative, later-drawn specimens should be tested. AQP4-IgG–seronegative NMO is less frequent than previously reported and is clinically similar to AQP4-IgG–seropositive NMO.

A Genome-Wide Association Study of Red Blood Cell Traits Using the Electronic Medical Record

Background The Electronic Medical Record (EMR) is a potential source for high throughput phenotyping to conduct genome-wide association studies (GWAS), including those of medically relevant quantitative traits. We describe use of the Mayo Clinic EMR to conduct a GWAS of red blood cell (RBC) traits in a cohort of patients with peripheral arterial disease (PAD) and controls without PAD. Methodology and Principal Findings Results for hemoglobin level, hematocrit, RBC count, mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration were extracted from the EMR from January 1994 to September 2009. Out of 35,159 RBC trait values in 3,411 patients, we excluded 12,864 values in 1,165 patients that had been measured during hospitalization or in the setting of hematological disease, malignancy, or use of drugs that affect RBC traits, leaving a final genotyped sample of 3,012, 80% of whom had ≥2 measurements. The median of each RBC trait was used in the genetic analyses, which were conducted using an additive model that adjusted for age, sex, and PAD status. We identified four genomic loci that were associated (P<5×10−8) with one or more of the RBC traits (HBLS1/MYB on 6q23.3, TMPRSS6 on 22q12.3, HFE on 6p22.1, and SLC17A1 on 6p22.2). Three of these loci (HBLS1/MYB, TMPRSS6, and HFE) had been identified in recent GWAS and the allele frequencies, effect sizes, and the directions of effects of the replicated SNPs were similar to the prior studies. Conclusions Our results demonstrate feasibility of using the EMR to conduct high throughput genomic studies of medically relevant quantitative traits.

Billing code algorithms to identify cases of peripheral artery disease from administrative data

Objective To construct and validate billing code algorithms for identifying patients with peripheral arterial disease (PAD). Methods We extracted all encounters and line item details including PAD-related billing codes at Mayo Clinic Rochester, Minnesota, between July 1, 1997 and June 30, 2008; 22 712 patients evaluated in the vascular laboratory were divided into training and validation sets. Multiple logistic regression analysis was used to create an integer code score from the training dataset, and this was tested in the validation set. We applied a model-based code algorithm to patients evaluated in the vascular laboratory and compared this with a simpler algorithm (presence of at least one of the ICD-9 PAD codes 440.20–440.29). We also applied both algorithms to a community-based sample (n=4420), followed by a manual review. Results The logistic regression model performed well in both training and validation datasets (c statistic=0.91). In patients evaluated in the vascular laboratory, the model-based code algorithm provided better negative predictive value. The simpler algorithm was reasonably accurate for identification of PAD status, with lesser sensitivity and greater specificity. In the community-based sample, the sensitivity (38.7% vs 68.0%) of the simpler algorithm was much lower, whereas the specificity (92.0% vs 87.6%) was higher than the model-based algorithm. Conclusions A model-based billing code algorithm had reasonable accuracy in identifying PAD cases from the community, and in patients referred to the non-invasive vascular laboratory. The simpler algorithm had reasonable accuracy for identification of PAD in patients referred to the vascular laboratory but was significantly less sensitive in a community-based sample.

Accelerated Accumulation of Multimorbidity After Bilateral Oophorectomy: A Population-Based Cohort Study

Objective To study the association between bilateral oophorectomy and the rate of accumulation of multimorbidity. Patients and Methods In this historical cohort study, the Rochester Epidemiology Project records-linkage system was used to identify all premenopausal women who underwent bilateral oophorectomy before age 50 years between January 1, 1988, and December 31, 2007, in Olmsted County, Minnesota. Each woman was randomly matched to a referent woman born in the same year (± 1 year) who had not undergone bilateral oophorectomy. We studied the rate of accumulation of 18 common chronic conditions over a median of approximately 14 years of follow-up. Results Although women who underwent bilateral oophorectomy already had a higher multimorbidity burden at the time of oophorectomy, they also experienced a significantly increased risk of subsequent multimorbidity (P=.XX). After adjustments for 18 chronic conditions present at baseline, race/ethnicity, education, body mass index, smoking, age at baseline, and calendar year at baseline, women who underwent oophorectomy before age 46 years experienced an increased risk of depression, hyperlipidemia, cardiac arrhythmias, coronary artery disease, arthritis, asthma, chronic obstructive pulmonary disease, and osteoporosis. In addition, they experienced an accelerated rate of accumulation of the 18 chronic conditions considered together (hazard ratio, 1.22; 95% CI, 1.14–1.31; P<.001). Several of these associations were reduced in women who received estrogen therapy. Conclusion Bilateral oophorectomy is associated with a higher risk of multimorbidity, even after adjustment for conditions present at baseline and for several possible confounders. However, several of these associations were reduced in women who received estrogen therapy.

Disease location is associated with survival in patients with peripheral arterial disease.

Background We investigated whether disease location influences survival in patients with peripheral arterial disease. Methods and Results Patients (n=12 731; mean age, 67.5±12.7 years; 57.4% male) who underwent outpatient noninvasive lower extremity arterial evaluation were followed up for 5.9±3.1 years for all‐cause mortality. Peripheral arterial disease (n=8930) was defined as a resting or postexercise ankle‐brachial index (ABI) ≤0.90, and normal ABI (n=3 801) was defined as a resting and postexercise ABI of 1.00 to 1.30. Presence or absence of disease at the proximal location or distal location was determined on the basis of Doppler signals in leg arteries; 42% had no PD or DD, 45% had proximal (14% postexercise PD only), 30% had distal disease, 17% had both proximal and distal disease, 28% had proximal only and 14% had distal only. We performed multivariable logistic regression to identify factors associated with disease location, and Cox proportional hazard regression to assess the respective effects of proximal or distal disease on survival. Older age, male sex, diabetes, heart failure, and critical limb ischemia were associated with distal disease, whereas female sex, smoking, hypertension, dyslipidemia, coronary heart disease, cerebrovascular disease, chronic obstructive pulmonary disease, and critical limb ischemia were associated with proximal disease. Over a mean follow‐up of 5.9±3.1 years, 3039 patients (23.9%) died. After adjustment for potential confounders, the hazard ratios (HRs) of death associated with PD only and DD only were 1.3 (1.3 to 1.4) and 1.5 (1.4 to 1.6), respectively. After additional adjustment for resting ABI, there was no significant association between proximal disease and death, whereas the association of distal disease with death remained significant (HR, 1.2; 95% CI, 1.1 to 1.3). Conclusions In patients with peripheral arterial disease, proximal and distal disease locations were associated with distinctive risk factor and comorbidity profiles. Distal disease was associated with worse survival even after adjustment for risk factors, comorbidities, and resting ABI.

Neural autoantibody clusters aid diagnosis of cancer

Purpose: Clustering of neural autoantibodies in patients with paraneoplastic neurologic disorders may predict tumor type. A mathematical analysis of neural autoantibody clusters was performed in 78,889 patients undergoing evaluation for a suspected paraneoplastic autoimmune neurologic disorder. Tumor predictive autoantibody profiles were confirmed in sera from patients with histologically proven tonsillar cancer, thymoma, and lung cancer. Patients and Methods: Of note, 78,889 patient sera were tested for 15 defined neural autoantibodies (1.2 million tests). The observed and hypothesized frequencies of autoantibody clusters were compared and their tumor associations defined. A tumor validation study comprised serum from 368 patients with a variety of tumors (thymoma, lung, or tonsil). Results: Informative oncological associations included (i) thymoma in 85% of patients with muscle striational, acetylcholine receptor antibodies plus CRMP5 autoantibodies; (ii) lung carcinoma in 80% with both P/Q-type and N-type calcium channel antibodies plus SOX1-IgG; and (iii) in men, prostate carcinoma frequency more than doubled when striational and muscle AChR specificities were accompanied by ganglionic AChR antibody. In women, amphiphysin-IgG alone was associated commonly with breast carcinoma, but amphiphysin-IgG, coexisting with antineuronal nuclear autoantibody-type 1 or CRMP5-IgG, was associated with lung cancer (P < 0.0001). In the validation cohorts, many tumor-associated profiles were encountered that matched the clusters identified in the screening study (e.g., 15% of thymoma patients had striational, acetylcholine receptor antibodies plus collapsin response-mediator protein-5 autoantibodies). Conclusions: Neural autoantibodies commonly coexist in specific clusters that are identifiable by comprehensive screening. Signature autoantibody clusters may predict a patients cancer risk and type. Clin Cancer Res; 20(14); 3862–9. ©2014 AACR.

Reference and Interpretive Ranges for α1-Antitrypsin Quantitation by Phenotype in Adult and Pediatric Populations

Laboratory evaluation of α(1)-antitrypsin (A1AT) deficiency involves measurement of circulating A1AT protein (quantitation) and characterization of A1AT genetic polymorphisms (phenotyping or genotyping). This study compared adult and pediatric A1AT reference ranges in patients with nondeficiency alleles and examined A1AT concentrations in multiple other phenotypes. A1AT phenotype and quantitation were retrospectively collected on adult (n = 21,444) and pediatric (n = 2,469) samples that were submitted for laboratory evaluation of A1AT deficiency. The 95% reference ranges for normal adult and pediatric populations with the M/M phenotype were determined to be 100 to 273 mg/dL (18.4-50.2 μmol/L) and 93 to 251 mg/dL (17.1-46.2 μmol/L), respectively (P < .0001). Decreased concentrations of A1AT correlated with heterozygosity and homozygosity for the S and Z alleles in both the adult and pediatric groups. Other rare alleles, such as I, were also associated with decreased concentrations of A1AT, particularly in the context of a Z allele, and may warrant monitoring for symptoms of deficiency.

Increased incidence and recurrence rates of nonmelanoma skin cancer in patients with non-Hodgkin lymphoma: A Rochester Epidemiology Project population-based study in Minnesota

BACKGROUND Cutaneous malignancy is associated with worse outcomes in patients with chronic lymphocytic leukemia (CLL). OBJECTIVE We sought to identify the incidence and recurrence rate of nonmelanoma skin cancer (NMSC) in patients with non-Hodgkin lymphoma (NHL). METHODS NMSC incidence was calculated and Cox proportional hazards models were used to evaluate associations with risk of recurrence for patients with NHL between 1976 and 2005 who were in the Rochester Epidemiology Project research infrastructure. RESULTS We identified 282 patients with CLL or small lymphocytic lymphoma and 435 with non-CLL NHL. The incidence of basal cell carcinoma and squamous cell carcinoma was 1829.3 (95% confidence interval [CI] 1306.7-2491.1) and 2224.9 (95% CI 1645.9-2941.6), respectively, in patients with CLL. The cumulative recurrence rate at 8 years after treatment with Mohs micrographic surgery was 8.3% (95% CI 0.0%-22.7%) for basal cell carcinoma and 13.4% (95% CI 0.0%-25.5%) for squamous cell carcinoma in patients with CLL. LIMITATIONS This was a retrospective cohort study. CONCLUSIONS After Mohs micrographic surgery and standard excision of NMSC, patients with NHL had a skin cancer recurrence rate that was higher than expected. Careful treatment and monitoring of patients with NHL and NMSC are warranted.

Autoimmune encephalitis epidemiology and a comparison to infectious encephalitis

To evaluate the incidence and prevalence of autoimmune encephalitis and compare it to that of infectious encephalitis.