Melanoma Detection in Alaska Native, American Indian, Asian, Black, Hispanic, and Pacific Islander Patients in a Large Skin Cancer Screening Initiative.

This cohort study investigates patterns in melanoma detection in racial and ethnic minority populations as part of a large, primary care­based screening initiative.

Improvement of Unilateral Breast Hypoplasia With Oral Spironolactone in a Patient With Becker Nevus Syndrome.

Becker nevus (BN) is a benign cutaneous smooth muscle hamartoma that presents with a hyperpigmented patch or plaque with or without hypertrichosis.1 BN may be associated with ipsilateral breast hypoplasia or other musculoskeletal abnormalities, an association which has been termed Becker nevus syndrome (BNS).

Five-Year Outcomes of a Melanoma Screening Initiative in a Large Health Care System.

Importance: Population-based skin cancer screening is currently not recommended owing to lack of data to quantify the balance of benefits and harms. Objective: To compare thickness-specific incidence of melanoma in screened vs unscreened patients following the initiation of a primary care-based skin cancer screening initiative. Design, Setting, and Participants: This observational study of a quality improvement initiative was conducted from January 1, 2014, through December 31, 2018, among patients 35 years and older presenting for a primary care visit at primary care practices within an academic and community-based health care system during the study period. Data analysis was performed January 2020 to January 2022. Interventions: Primary care clinicians were offered training in melanoma identification through skin examination and encouraged to offer annual screening to patients 35 years and older. Main Outcomes and Measures: Thickness of melanomas diagnosed in screened and unscreened patients. Results: Among 595 799 analyzed screen-eligible patients, 144 851 (24.3%) were screened at least once. Screened patients were older (median [IQR] age, 59 [49-67] vs 55 [45-66] years) and more likely to be female (82 244 [56.8%] vs 250 806 [55.6%]; P < .001) and non-Hispanic White (124 747 [86.1%] vs 375 890 [83.4%]; P < .001) than unscreened patients. After adjusting for age, sex, and race, screened patients were more likely than unscreened patients to be diagnosed with in situ (incidence, 30.4 vs 14.4; hazard ratio [HR], 2.6; 95% CI, 2.1-3.1; P < .001) or thin invasive (≤1 mm) melanoma (incidence, 24.5 vs 16.1; HR, 1.8; 95% CI, 1.5-2.2; P < .001). Screened patients were also more likely than unscreened patients to be diagnosed with in situ (incidence, 26.7 vs 12.9; HR, 2.1; 95% CI, 1.7-2.6; P < .001) or thin invasive (≤1 mm) interval melanomas (melanoma diagnosed at least 60 days after initial screening examination) (incidence, 18.5 vs 14.4; HR, 1.3; 95% CI, 1.0-1.7; P = .03). Incidence of melanoma thicker than 4 mm in unscreened and screened patients, respectively, was 3.3 and 2.7 (HR, 0.8; 95% CI, 0.4-1.4; P = .38) for all melanomas and 2.7 and 1.5 (HR, 0.6; 95% CI, 0.2-1.2; P = .15) for interval melanomas. Conclusions and Relevance: In this quality improvement study, primary care-based melanoma screening was associated with increased detection of thin melanoma, raising concern about overdiagnosis. Further studies with longer follow-up are needed to determine the influence of screening on the incidence of thick melanoma and outcomes associated with high costs and poor outcomes, such as metastasis.

Factors predicting outcomes of patients with high-risk squamous cell carcinoma treated with Mohs micrographic surgery.

BACKGROUND: There is limited literature on the long-term outcomes and prognostic factors of high-risk cutaneous squamous cell carcinomas (hrSCC) treated with Mohs micrographic surgery (MMS). OBJECTIVE: To determine the rates of local recurrence, metastatic disease, and disease-specific death in hrSCCs treated with MMS and patient or tumor factors associated with poor outcomes. METHODS: Single-institution, retrospective cohort analysis of hrSCC treated with MMS alone and MMS with adjuvant therapy. RESULTS: A total of 882 cases of hrSCC treated with MMS were identified, of which 842 were treated with MMS alone, with a median follow-up time of 2.4 years. The rate of local recurrence was 2.5%, of metastatic disease was 1.9%, and of disease-specific death was 0.57%. Perineural invasion, poor differentiation, and immunosuppression were significantly associated with poor outcomes. In propensity score-matched case patients treated with adjuvant therapy and control patients treated with Mohs alone, there was no significant difference in progression-free survival, but matching was imperfect. LIMITATIONS: Single-institution, retrospective review. CONCLUSIONS: MMS remains an effective treatment for hrSCC. Current SCC staging systems may be limited by inconsistent inclusion of poor differentiation. Immunosuppression, especially transplant, should be considered a high-risk clinical feature. Further study is needed on the effect of adjuvant treatment.

Accuracy of Skin Cancer Diagnosis by Physician Assistants Compared With Dermatologists in a Large Health Care System.

Importance: Physician assistants (PAs) are increasingly used in dermatology practices to diagnose skin cancers, although, to date, their diagnostic accuracy compared with board-certified dermatologists has not been well studied. Objective: To compare diagnostic accuracy for skin cancer of PAs with that of dermatologists. Design, Setting, and Participants: Medical record review of 33 647 skin cancer screening examinations in 20 270 unique patients who underwent screening at University of Pittsburgh Medical Center-affiliated dermatology offices from January 1, 2011, to December 31, 2015. International Classification of Diseases, Ninth Revision code V76.43 and International Classification of Diseases and Related Health Problems, Tenth Revision code Z12.83 were used to identify pathology reports from skin cancer screening examinations by dermatologists and PAs. Exposure: Examination performed by a PA or dermatologist. Main Outcomes and Measures: Number needed to biopsy (NNB) to diagnose skin cancer (nonmelanoma, invasive melanoma, or in situ melanoma). Results: Of 20 270 unique patients, 12 722 (62.8%) were female, mean (SD) age at the first visit was 52.7 (17.4) years, and 19 515 patients (96.3%) self-reported their race/ethnicity as non-Hispanic white. To diagnose 1 case of skin cancer, the NNB was 3.9 for PAs and 3.3 for dermatologists (P < .001). Per diagnosed melanoma, the NNB was 39.4 for PAs and 25.4 for dermatologists (P = .007). Patients screened by a PA were significantly less likely than those screened by a dermatologist to be diagnosed with melanoma in situ (1.1% vs 1.8% of visits, P = .02), but differences were not significant for invasive melanoma (0.7% vs 0.8% of visits, P = .83) or nonmelanoma skin cancer (6.1% vs 6.1% of visits, P = .98). Conclusions and Relevance: Compared with dermatologists, PAs performed more skin biopsies per case of skin cancer diagnosed and diagnosed fewer melanomas in situ, suggesting that the diagnostic accuracy of PAs may be lower than that of dermatologists. Although the availability of PAs may help increase access to care and reduce waiting times for appointments, these findings have important implications for the training, appropriate scope of practice, and supervision of PAs and other nonphysician practitioners in dermatology.

Comparing Electrical Stimulation With and Without Ultrasound Guidance for Phenol Neurolysis to the Musculocutaneous Nerve.

BACKGROUND: Ultrasound guidance is increasingly being used for neurolytic procedures that have traditionally been done with electrical stimulation (e-stim) guidance alone. Ultrasound visualization with e-stim-guided neurolysis can potentially allow adjustments in injection protocols that will reduce the volume of neurolytic agent needed to achieve clinical improvement. OBJECTIVE: This study compared e-stim only to e-stim with ultrasound guidance in phenol neurolysis of the musculocutaneous nerve (MCN) for elbow flexor spasticity. We also evaluated the ultrasound appearance of the MCN in this population. DESIGN: Retrospective review. SETTING: University hospital outpatient clinic. PARTICIPANTS: Adults (N = 167) receiving phenol neurolysis to the MCN for treatment of elbow flexor spasticity between 1997 and 2014 and adult control subjects. METHODS: For each phenol injection of the MCN, the method of guidance, volume of phenol injected, technical success, improved range of motion at the elbow postinjection, adverse effects, reason for termination of injections, and details of concomitant botulinum toxin injection were recorded. The ultrasound appearance of the MCN, including nerve cross-sectional area and shape, were recorded and compared between groups. MAIN OUTCOME MEASURES: The volume of phenol injected and MCN cross-sectional area and shape as demonstrated by ultrasound. RESULTS: The addition of ultrasound to e-stim-guided phenol neurolysis was associated with lower doses of phenol when compared to e-stim guidance alone (2.31 mL versus 3.69 mL, P < .001). With subsequent injections, the dose of phenol increased with e-stim guidance (P < .001), but not with e-stim and ultrasound guidance (P = .95). Both methods of guidance had high technical success, improved ROM at elbow postinjection, and low rates of adverse events. In comparing the ultrasound appearance of the MCN in patients with spasticity to that of normal controls, there was no difference in the cross-sectional area of the nerve, but there was more variability in shape. CONCLUSIONS: Combined e-stim and ultrasound guidance during phenol neurolysis to the MCN allows a smaller volume of phenol to be used for equal effect, both at initial and repeat injection. The MCN shape was more variable in individuals with spasticity; this should be recognized so as to successfully locate the nerve to perform neurolysis. LEVEL OF EVIDENCE: IV.

Estimating the cost of skin cancer detection by dermatology providers in a large health care system.

BACKGROUND: Data on the cost and efficiency of skin cancer detection through total body skin examination are scarce. OBJECTIVE: To determine the number needed to screen (NNS) and biopsy (NNB) and cost per skin cancer diagnosed in a large dermatology practice in patients undergoing total body skin examination. METHODS: This is a retrospective observational study. RESULTS: During 2011-2015, a total of 20,270 patients underwent 33,647 visits for total body skin examination; 9956 lesion biopsies were performed yielding 2763 skin cancers, including 155 melanomas. The NNS to detect 1 skin cancer was 12.2 (95% confidence interval [CI] 11.7-12.6) and 1 melanoma was 215 (95% CI 185-252). The NNB to detect 1 skin cancer was 3.0 (95% CI 2.9-3.1) and 1 melanoma was 27.8 (95% CI 23.3-33.3). In a multivariable model for NNS, age and personal history of melanoma were significant factors. Age switched from a protective factor to a risk factor at 51 years of age. The estimated cost per melanoma detected was $32,594 (95% CI $27,326-$37,475). LIMITATIONS: Data are from a single health care system and based on physician coding. CONCLUSION: Melanoma detection through total body skin examination is most efficient in patients ≥50 years of age and those with a personal history of melanoma. Our findings will be helpful in modeling the cost effectiveness of melanoma screening by dermatologists.

Regulating drivers with epilepsy in Maryland: Results of the application of a United States consensus guideline.

OBJECTIVE: Driving regulations for people with seizures vary widely throughout the United States and the world. Maryland updated their guidelines in 2003 to reflect those of a U.S. consensus guideline requiring a minimum 3-month seizure-free period as well as an individual risk assessment by a Medical Advisory Board (MAB). This retrospective study provides the first analysis of outcomes after the implementation of the consensus guidelines and an assessment of their predictive validity through longitudinal outcome data. METHODS: MAB reviews and licensing records for Maryland driver applicants with seizures between 2004 and 2005 were reviewed, during which 254 first-time applicants were processed. The initial licensing decisions were assessed and the subsequent seizure recurrence and crash rates over the following 7 years were evaluated. RESULTS: The MAB approved driving for 74.8% of initial applicants; most had been seizure-free for over 6 months. Approved drivers had a longer median seizure-free period (563 days) compared to those who were denied (104.5 days, p < 0.01), and 22.7% of approved drivers had seizures recur during monitoring over the next year, although none resulted in crashes or deaths. Of applicants initially denied (n = 50), 89.3% were eventually licensed. Treating physicians recommended driving for 84.4% of applicants rejected by the MAB. SIGNIFICANCE: Maryland's individualized system for assessing driving applicants with seizures resulted in a dynamic process of approvals and denials based on favorable and unfavorable risk factors and lengths of seizure freedom. Seizure recurrences were comparable to internationally accepted rates. Over the course of monitoring, most applicants were eventually licensed. Treating physicians recommended that nearly all their patient applicants be permitted to drive, which raises safety concerns for the 10 states that rely solely on physician recommendations. Further assessment is needed of the risk factors deemed favorable and unfavorable by the U.S. consensus guidelines.

Multifocal primary cutaneous nodular amyloidosis.

Nodular cutaneous amyloidosis (NCA), the least common form of primary cutaneous amyloidosis, is characterized clinically by waxy, purpuric plaques and nodules and histologically by amyloid deposits in the dermis and subcutaneous tissue. We present a patient who developed multiple, non-contiguous NCA lesions over a three year period without evidence of systemic disease. We reviewed the literature and found few other cases of this unusual presentation.

NFAT5 and SLC4A10 Loci Associate with Plasma Osmolality.

Disorders of water balance, an excess or deficit of total body water relative to body electrolyte content, are common and ascertained by plasma hypo- or hypernatremia, respectively. We performed a two-stage genome-wide association study meta-analysis on plasma sodium concentration in 45,889 individuals of European descent (stage 1 discovery) and 17,637 additional individuals of European descent (stage 2 replication), and a transethnic meta-analysis of replicated single-nucleotide polymorphisms in 79,506 individuals (63,526 individuals of European descent, 8765 individuals of Asian Indian descent, and 7215 individuals of African descent). In stage 1, we identified eight loci associated with plasma sodium concentration at P<5.0 × 10-6 Of these, rs9980 at NFAT5 replicated in stage 2 meta-analysis (P=3.1 × 10-5), with combined stages 1 and 2 genome-wide significance of P=5.6 × 10-10 Transethnic meta-analysis further supported the association at rs9980 (P=5.9 × 10-12). Additionally, rs16846053 at SLC4A10 showed nominally, but not genome-wide, significant association in combined stages 1 and 2 meta-analysis (P=6.7 × 10-8). NFAT5 encodes a ubiquitously expressed transcription factor that coordinates the intracellular response to hypertonic stress but was not previously implicated in the regulation of systemic water balance. SLC4A10 encodes a sodium bicarbonate transporter with a brain-restricted expression pattern, and variant rs16846053 affects a putative intronic NFAT5 DNA binding motif. The lead variants for NFAT5 and SLC4A10 are cis expression quantitative trait loci in tissues of the central nervous system and relevant to transcriptional regulation. Thus, genetic variation in NFAT5 and SLC4A10 expression and function in the central nervous system may affect the regulation of systemic water balance.

Genome-wide study of resistant hypertension identified from electronic health records.

Resistant hypertension is defined as high blood pressure that remains above treatment goals in spite of the concurrent use of three antihypertensive agents from different classes. Despite the important health consequences of resistant hypertension, few studies of resistant hypertension have been conducted. To perform a genome-wide association study for resistant hypertension, we defined and identified cases of resistant hypertension and hypertensives with treated, controlled hypertension among >47,500 adults residing in the US linked to electronic health records (EHRs) and genotyped as part of the electronic MEdical Records & GEnomics (eMERGE) Network. Electronic selection logic using billing codes, laboratory values, text queries, and medication records was used to identify resistant hypertension cases and controls at each site, and a total of 3,006 cases of resistant hypertension and 876 controlled hypertensives were identified among eMERGE Phase I and II sites. After imputation and quality control, a total of 2,530,150 SNPs were tested for an association among 2,830 multi-ethnic cases of resistant hypertension and 876 controlled hypertensives. No test of association was genome-wide significant in the full dataset or in the dataset limited to European American cases (n = 1,719) and controls (n = 708). The most significant finding was CLNK rs13144136 at p = 1.00x10-6 (odds ratio = 0.68; 95% CI = 0.58-0.80) in the full dataset with similar results in the European American only dataset. We also examined whether SNPs known to influence blood pressure or hypertension also influenced resistant hypertension. None was significant after correction for multiple testing. These data highlight both the difficulties and the potential utility of EHR-linked genomic data to study clinically-relevant traits such as resistant hypertension.

Melorheostosis: A Retrospective Clinical Analysis of 24 Patients at the Mayo Clinic.

BACKGROUND: Current understanding of the clinical features of persons with melorheostosis is restricted primarily to individual case reports and small case series. OBJECTIVE: To assess the clinical features of patients with melorheostosis treated at our institution from 1972 through 2010. DESIGN: Chart review. SETTING: Tertiary academic medical center. PARTICIPANTS: Twenty-three patients with "definite" and one patient with "probable" melorheostosis based on radiographic criteria. METHODS: The eligible study cohort was identified through the Rochester Medical Index database. Further diagnostic confirmation of patients with melorheostosis was performed by radiographic review. MAIN OUTCOME MEASUREMENTS: We evaluated age at first visit to our institution, gender, affected body area, number of bones affected, presenting symptoms, surgical evaluation, and therapies provided. RESULTS: The average age at first evaluation at our clinic was 36.5 years (median 41.5 years, range 3-68 years). The female to male ratio was 4:1. The lower extremity was most commonly affected (66.6%), followed by upper extremity (33.3%), spine (16.6%), and head (8.3%). One-third of patients had involvement of a single bone; two-thirds had multiple bone involvement. Pain was the most common presenting concern (83.3%), followed by deformity (54.1%), limitation of movement (45.8%), numbness (37.5%), and weakness (25.0%). Most patients had a physician evaluation (87.5%); patients also underwent orthopedic surgery (45.8%), physical therapy (33.3%), and occupational therapy (12.5%). CONCLUSIONS: Melorheostosis is a rare sclerotic bone disease resulting in pain, deformity, and dysfunction. An interdisciplinary approach to care should include nonoperative and operative evaluation, as well as appropriate therapies. A prospective approach to evaluation, including imaging and physical examinations, would provide valuable longitudinal data. LEVEL OF EVIDENCE: IV.

New antiepileptic drug safety information is not transmitted systematically and accepted by U.S. neurologists.

We surveyed U.S. neurologists in order to evaluate their knowledge of, and sources for, recent FDA safety warnings regarding antiepileptic drugs (AEDs) and whether they incorporate this information into their practices. Survey respondents (N=505) were predominantly board-certified American Academy of Neurology members. Approximately 20% of respondent neurologists were not aware of warnings about four drug safety risks: suicidality with newer AEDs, increased birth defect risks from in utero divalproex exposure, impaired cognitive development from in utero divalproex exposure, and the requirement of haplotype screening in patients of Asian descent starting carbamazepine. Most respondents were aware of a recommendation for haplotype screening, yet did not routinely perform the safety screening, and 18 reported patients that had hypersensitivity reactions to carbamazepine. Respondents learned about drug safety risks from varied sources; only notifications from specialty organizations were associated with accurate knowledge of drug safety warnings. Most surveyed neurologists would prefer implementing "a formal warning process via specialty organizations" with e-mails of updated product insert warnings.

Pitfalls of merging GWAS data: lessons learned in the eMERGE network and quality control procedures to maintain high data quality.

Genome-wide association studies (GWAS) are a useful approach in the study of the genetic components of complex phenotypes. Aside from large cohorts, GWAS have generally been limited to the study of one or a few diseases or traits. The emergence of biobanks linked to electronic medical records (EMRs) allows the efficient reuse of genetic data to yield meaningful genotype-phenotype associations for multiple phenotypes or traits. Phase I of the electronic MEdical Records and GEnomics (eMERGE-I) Network is a National Human Genome Research Institute-supported consortium composed of five sites to perform various genetic association studies using DNA repositories and EMR systems. Each eMERGE site has developed EMR-based algorithms to comprise a core set of 14 phenotypes for extraction of study samples from each site's DNA repository. Each eMERGE site selected samples for a specific phenotype, and these samples were genotyped at either the Broad Institute or at the Center for Inherited Disease Research using the Illumina Infinium BeadChip technology. In all, approximately 17,000 samples from across the five sites were genotyped. A unified quality control (QC) pipeline was developed by the eMERGE Genomics Working Group and used to ensure thorough cleaning of the data. This process includes examination of sample and marker quality and various batch effects. Upon completion of the genotyping and QC analyses for each site's primary study, eMERGE Coordinating Center merged the datasets from all five sites. This larger merged dataset reentered the established eMERGE QC pipeline. Based on lessons learned during the process, additional analyses and QC checkpoints were added to the pipeline to ensure proper merging. Here, we explore the challenges associated with combining datasets from different genotyping centers and describe the expansion to eMERGE QC pipeline for merged datasets. These additional steps will be useful as the eMERGE project expands to include additional sites in eMERGE-II, and also serve as a starting point for investigators merging multiple genotype datasets accessible through the National Center for Biotechnology Information in the database of Genotypes and Phenotypes. Our experience demonstrates that merging multiple datasets after additional QC can be an efficient use of genotype data despite new challenges that appear in the process.

Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.

BACKGROUND: Dilated cardiomyopathy (DCM) is a heritable, genetically heterogeneous disorder that typically exhibits autosomal dominant inheritance. Genomic strategies enable discovery of novel, unsuspected molecular underpinnings of familial DCM. We performed genome-wide mapping and exome sequencing in a unique family wherein DCM segregated as an autosomal recessive (AR) trait. METHODS AND RESULTS: Echocardiography in 17 adult descendants of first cousins revealed DCM in 2 female siblings and idiopathic left ventricular enlargement in their brother. Genotyping and linkage analysis mapped an AR DCM locus to chromosome arm 7q21, which was validated and refined by high-density homozygosity mapping. Exome sequencing of the affected sisters was then used as a complementary strategy for mutation discovery. An iterative bioinformatics process was used to filter >40,000 genetic variants, revealing a single shared homozygous missense mutation localized to the 7q21 critical region. The mutation, absent in HapMap, 1000 Genomes, and 474 ethnically matched controls, altered a conserved residue of GATAD1, encoding GATA zinc finger domain-containing protein 1. Thirteen relatives were heterozygous mutation carriers with no evidence of myocardial disease, even at advanced ages. Immunohistochemistry demonstrated nuclear localization of GATAD1 in left ventricular myocytes, yet subcellular expression and nuclear morphology were aberrant in the proband. CONCLUSIONS: Linkage analysis and exome sequencing were used as synergistic genomic strategies to identify GATAD1 as a gene for AR DCM. GATAD1 binds to a histone modification site that regulates gene expression. Consistent with murine DCM caused by genetic disruption of histone deacetylases, the data implicate an inherited basis for epigenetic dysregulation in human heart failure.

Variants near FOXE1 are associated with hypothyroidism and other thyroid conditions: using electronic medical records for genome- and phenome-wide studies.

We repurposed existing genotypes in DNA biobanks across the Electronic Medical Records and Genomics network to perform a genome-wide association study for primary hypothyroidism, the most common thyroid disease. Electronic selection algorithms incorporating billing codes, laboratory values, text queries, and medication records identified 1317 cases and 5053 controls of European ancestry within five electronic medical records (EMRs); the algorithms' positive predictive values were 92.4% and 98.5% for cases and controls, respectively. Four single-nucleotide polymorphisms (SNPs) in linkage disequilibrium at 9q22 near FOXE1 were associated with hypothyroidism at genome-wide significance, the strongest being rs7850258 (odds ratio [OR] 0.74, p = 3.96 × 10(-9)). This association was replicated in a set of 263 cases and 1616 controls (OR = 0.60, p = 5.7 × 10(-6)). A phenome-wide association study (PheWAS) that was performed on this locus with 13,617 individuals and more than 200,000 patient-years of billing data identified associations with additional phenotypes: thyroiditis (OR = 0.58, p = 1.4 × 10(-5)), nodular (OR = 0.76, p = 3.1 × 10(-5)) and multinodular (OR = 0.69, p = 3.9 × 10(-5)) goiters, and thyrotoxicosis (OR = 0.76, p = 1.5 × 10(-3)), but not Graves disease (OR = 1.03, p = 0.82). Thyroid cancer, previously associated with this locus, was not significantly associated in the PheWAS (OR = 1.29, p = 0.09). The strongest association in the PheWAS was hypothyroidism (OR = 0.76, p = 2.7 × 10(-13)), which had an odds ratio that was nearly identical to that of the curated case-control population in the primary analysis, providing further validation of the PheWAS method. Our findings indicate that EMR-linked genomic data could allow discovery of genes associated with many diseases without additional genotyping cost.

Evaluating the influence of quality control decisions and software algorithms on SNP calling for the affymetrix 6.0 SNP array platform.

OBJECTIVE: Our goal was to evaluate the influence of quality control (QC) decisions using two genotype calling algorithms, CRLMM and Birdseed, designed for the Affymetrix SNP Array 6.0. METHODS: Various QC options were tried using the two algorithms and comparisons were made on subject and call rate and on association results using two data sets. RESULTS: For Birdseed, we recommend using the contrast QC instead of QC call rate for sample QC. For CRLMM, we recommend using the signal-to-noise rate ≥4 for sample QC and a posterior probability of 90% for genotype accuracy. For both algorithms, we recommend calling the genotype separately for each plate, and dropping SNPs with a lower call rate (<95%) before evaluating samples with lower call rates. To investigate whether the genotype calls from the two algorithms impacted the genome-wide association results, we performed association analysis using data from the GENOA cohort; we observed that the number of significant SNPs were similar using either CRLMM or Birdseed. CONCLUSIONS: Using our suggested workflow both algorithms performed similarly; however, fewer samples were removed and CRLMM took half the time to run our 854 study samples (4.2 h) compared to Birdseed (8.4 h).