Evaluation of an Algorithm for Identifying Ocular Conditions in Electronic Health Record Data.

Importance: For research involving big data, researchers must accurately identify patients with ocular diseases or phenotypes of interest. Reliance on administrative billing codes alone for this purpose is limiting. Objective: To develop a method to accurately identify the presence or absence of ocular conditions of interest using electronic health record (EHR) data. Design, Setting, and Participants: This study is a retrospective analysis of the EHR data of patients (n = 122 339) in the Sight Outcomes Research Collaborative Ophthalmology Data Repository who received eye care at participating academic medical centers between August 1, 2012, and August 31, 2017. An algorithm that searches structured and unstructured (free-text) EHR data for conditions of interest was developed and then tested to determine how well it could detect the presence or absence of exfoliation syndrome (XFS). The algorithm was trained to search for evidence of XFS among a sample of patients with and without XFS (n = 200) by reviewing International Classification of Diseases, Ninth Revision or International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-9 or ICD-10) billing codes, the patient's problem list, and text within the ocular examination section and unstructured (free-text) data in the EHR. The likelihood that each patient had XFS was estimated using logistic least absolute shrinkage and selection operator (LASSO) regression. The EHR data of all patients were run through the algorithm to generate an XFS probability score for each patient. The algorithm was validated with review of EHRs by glaucoma specialists. Main Outcomes and Measures: Positive predictive value (PPV) and negative predictive value (NPV) of the algorithm were computed as the proportion of patients correctly classified with XFS or without XFS. Results: This study included 122 339 patients, with a mean (SD) age of 52.4 (25.1) years. Of these patients, 69 002 (56.4%) were female and 99 579 (81.4%) were white. The algorithm assigned a less than 10% probability of XFS for 121 085 patients (99.0%) as well as an XFS probability score of more than 75% for 543 patients (0.4%), more than 90% for 353 patients (0.3%), and more than 99% for 83 patients (0.07%). Validated by glaucoma specialists, the algorithm had a PPV of 95.0% (95% CI, 89.5%-97.7%) and an NPV of 100% (95% CI, 91.2%-100%). When there was ICD-9 or ICD-10 billing code documentation of XFS, in 86% or 96% of the records, respectively, evidence of XFS was also recorded elsewhere in the EHR. Conversely, when there was clinical examination or free-text evidence of XFS, it was documented with ICD-9 codes only approximately 40% of the time and even less often with ICD-10 codes. Conclusions and Relevance: The algorithm developed, tested, and validated in this study appears to be better at identifying the presence or absence of XFS in EHR data than the conventional approach of assessing only billing codes; such an algorithm may enhance the ability of investigators to use EHR data to study patients with ocular diseases.

Common variants at 9p21 and 8q22 are associated with increased susceptibility to optic nerve degeneration in glaucoma.

Optic nerve degeneration caused by glaucoma is a leading cause of blindness worldwide. Patients affected by the normal-pressure form of glaucoma are more likely to harbor risk alleles for glaucoma-related optic nerve disease. We have performed a meta-analysis of two independent genome-wide association studies for primary open angle glaucoma (POAG) followed by a normal-pressure glaucoma (NPG, defined by intraocular pressure (IOP) less than 22 mmHg) subgroup analysis. The single-nucleotide polymorphisms that showed the most significant associations were tested for association with a second form of glaucoma, exfoliation-syndrome glaucoma. The overall meta-analysis of the GLAUGEN and NEIGHBOR dataset results (3,146 cases and 3,487 controls) identified significant associations between two loci and POAG: the CDKN2BAS region on 9p21 (rs2157719 [G], OR = 0.69 [95%CI 0.63-0.75], p = 1.86×10⁻¹8), and the SIX1/SIX6 region on chromosome 14q23 (rs10483727 [A], OR = 1.32 [95%CI 1.21-1.43], p = 3.87×10⁻¹¹). In sub-group analysis two loci were significantly associated with NPG: 9p21 containing the CDKN2BAS gene (rs2157719 [G], OR = 0.58 [95% CI 0.50-0.67], p = 1.17×10⁻¹²) and a probable regulatory region on 8q22 (rs284489 [G], OR = 0.62 [95% CI 0.53-0.72], p = 8.88×10⁻¹°). Both NPG loci were also nominally associated with a second type of glaucoma, exfoliation syndrome glaucoma (rs2157719 [G], OR = 0.59 [95% CI 0.41-0.87], p = 0.004 and rs284489 [G], OR = 0.76 [95% CI 0.54-1.06], p = 0.021), suggesting that these loci might contribute more generally to optic nerve degeneration in glaucoma. Because both loci influence transforming growth factor beta (TGF-beta) signaling, we performed a genomic pathway analysis that showed an association between the TGF-beta pathway and NPG (permuted p = 0.009). These results suggest that neuro-protective therapies targeting TGF-beta signaling could be effective for multiple forms of glaucoma.

Mutations in a BTB-Kelch protein, KLHL7, cause autosomal-dominant retinitis pigmentosa.

Retinitis pigmentosa (RP) refers to a genetically heterogeneous group of progressive neurodegenerative diseases that result in dysfunction and/or death of rod and cone photoreceptors in the retina. So far, 18 genes have been identified for autosomal-dominant (ad) RP. Here, we describe an adRP locus (RP42) at chromosome 7p15 through linkage analysis in a six-generation Scandinavian family and identify a disease-causing mutation, c.449G-->A (p.S150N), in exon 6 of the KLHL7 gene. Mutation screening of KLHL7 in 502 retinopathy probands has revealed three different missense mutations in six independent families. KLHL7 is widely expressed, including expression in rod photoreceptors, and encodes a 75 kDa protein of the BTB-Kelch subfamily within the BTB superfamily. BTB-Kelch proteins have been implicated in ubiquitination through Cullin E3 ligases. Notably, all three putative disease-causing KLHL7 mutations are within a conserved BACK domain; homology modeling suggests that mutant amino acid side chains can potentially fill the cleft between two helices, thereby affecting the ubiquitination complexes. Mutations in an identical region of another BTB-Kelch protein, gigaxonin, have previously been associated with giant axonal neuropathy. Our studies suggest an additional role of the ubiquitin-proteasome protein-degradation pathway in maintaining neuronal health and in disease.

Madeline 2.0 PDE: a new program for local and web-based pedigree drawing.

UNLABELLED: The Madeline 2.0 Pedigree Drawing Engine (PDE) is a pedigree drawing program for use in linkage and family-based association studies. The program is designed to handle large and complex pedigrees with an emphasis on readability and aesthetics. For complex pedigrees, we use a hybrid algorithm in which consanguinous loops are drawn as cyclic graphs whenever possible, but we resort to acyclic graphs when matings can no longer be connected without line crossings. A similar hybrid approach is used to avoid line crossings for matings between distant descendants of different founding groups. Written in object-oriented C++ and released under the GNU General Public License (GPL), Madeline 2.0 PDE reads input files specified on the command line and generates pedigree drawings without user interaction. Pedigree output in scalable vector graphics (SVG) format can be viewed in browsers with native SVG rendering support or in vector graphics editors. We provide an easy-to-use public web service, which is experimental and still under development. AVAILABILITY: http://kellogg.umich.edu/madeline.

Mutations in TCF8 cause posterior polymorphous corneal dystrophy and ectopic expression of COL4A3 by corneal endothelial cells.

Posterior polymorphous corneal dystrophy (PPCD, also known as PPMD) is a rare disease involving metaplasia and overgrowth of corneal endothelial cells. In patients with PPCD, these cells manifest in an epithelial morphology and gene expression pattern, produce an aberrant basement membrane, and, sometimes, spread over the iris and nearby structures in a way that increases the risk for glaucoma. We previously mapped PPCD to a region (PPCD3) on chromosome 10 containing the gene that encodes the two-handed zinc-finger homeodomain transcription factor TCF8. Here, we report a heterozygous frameshift mutation in TCF8 that segregates with PPCD in the family used to map PPCD3 and four different heterozygous nonsense and frameshift mutations in TCF8 in four other PPCD probands. Family reports of inguinal hernia, hydrocele, and possible bone anomalies in affected individuals suggest that individuals with TCF8 mutations should be examined for nonocular anomalies. We detect transcripts of all three identified PPCD genes (VSX1, COL8A2, and TCF8) in the cornea. We show presence of a complex (core plus secondary) binding site for TCF8 in the promoter of Alport syndrome gene COL4A3, which encodes collagen type IV alpha 3, and we present immunohistochemical evidence of ectopic expression of COL4A3 in corneal endothelium of the proband of the original PPCD3 family. Identification of TCF8 as the PPCD3 gene provides a valuable tool for the study of critical gene regulation events in PPCD pathology and suggests a possible role for TCF8 mutations in altered structure and function of cells lining body cavities other than the anterior chamber of the eye. Thus, this study has identified TCF8 as the gene responsible for approximately half of the cases of PPCD, has implicated TCF8 mutations in developmental abnormalities outside the eye, and has presented the TCF8 regulatory target, COL4A3, as a key, shared molecular component of two different diseases, PPCD and Alport syndrome.

A locus for posterior polymorphous corneal dystrophy (PPCD3) maps to chromosome 10.

Posterior polymorphous corneal dystrophy (PPCD) is an autosomal dominant disorder characterized by corneal endothelial abnormalities, which can lead to blindness due to loss of corneal transparency and sometimes glaucoma. We mapped a new locus responsible for PPCD in a family in which we excluded the previously reported PPCD locus on 20q11, and the region containing COL8A2 on chromosome 1. Results of a 317-marker genome scan provided significant evidence of linkage of PPCD to markers on chromosome 10, with single-point LOD scores of 2.63, 1.63, and 3.19 for markers D10S208 (at (circumflex)theta = 0.03), D10S1780 (at (circumflex)theta = 0.00), and D10S578 (at (circumflex)theta = 0.06). A maximum multi-point LOD score of 4.35 was found at marker D10S1780. Affected family members shared a haplotype in an 8.55 cM critical interval that was bounded by markers D10S213 and D10S578. Our finding of another PPCD locus, PPCD3, on chromosome 10 indicates that PPCD is genetically heterogeneous. Guttae, a common corneal finding sometimes observed along with PPCD, were found among both affected and unaffected members of the proband's sib ship, but were absent in the younger generations of the family. Evaluation of phenotypic differences between family members sharing the same affected haplotype raises questions about whether differences in disease severity, including differences in response to surgical interventions, could be due to genetic background or other factors independent of the PPCD3 locus.

Age-related macular degeneration: a high-resolution genome scan for susceptibility loci in a population enriched for late-stage disease.

Age-related macular degeneration (AMD) is a complex multifactorial disease that affects the central region of the retina. AMD is clinically heterogeneous, leading to geographic atrophy (GA) and/or choroidal neovascularization (CNV) at advanced stages. Considerable data exists in support of a genetic predisposition for AMD. Recent linkage studies have provided evidence in favor of several AMD susceptibility loci. We have performed a high-resolution (5-cM) genome scan of 412 affected relative pairs that were enriched for late-stage disease (GA and/or CNV). Nonparametric linkage analysis was performed using two different diagnostic criteria and also by dividing the affected individuals according to GA or CNV phenotype. Our results demonstrate evidence of linkage in regions that were suggested in at least one previous study at chromosomes 1q (236-240 cM in the Marshfield genetic map), 5p (40-50 cM), and 9q (111 cM). Multipoint analysis of affected relatives with CNV provided evidence of additional susceptibility loci on chromosomes 2p (10 cM) and 22q (25 cM). A recently identified Gln5345Arg change in HEMICENTIN-1 on chromosome 1q25 was not detected in 274 affected members in the restricted group with AMD, 346 additional patients with AMD, and 237 unaffected controls. Our results consolidate the chromosomal locations of several AMD susceptibility loci and, together with previous reports, should facilitate the search for disease-associated sequence variants.