James G. Linneman

Importance of multi-modal approaches to effectively identify cataract cases from electronic health records

OBJECTIVE There is increasing interest in using electronic health records (EHRs) to identify subjects for genomic association studies, due in part to the availability of large amounts of clinical data and the expected cost efficiencies of subject identification. We describe the construction and validation of an EHR-based algorithm to identify subjects with age-related cataracts. MATERIALS AND METHODS We used a multi-modal strategy consisting of structured database querying, natural language processing on free-text documents, and optical character recognition on scanned clinical images to identify cataract subjects and related cataract attributes. Extensive validation on 3657 subjects compared the multi-modal results to manual chart review. The algorithm was also implemented at participating electronic MEdical Records and GEnomics (eMERGE) institutions. RESULTS An EHR-based cataract phenotyping algorithm was successfully developed and validated, resulting in positive predictive values (PPVs) >95%. The multi-modal approach increased the identification of cataract subject attributes by a factor of three compared to single-mode approaches while maintaining high PPV. Components of the cataract algorithm were successfully deployed at three other institutions with similar accuracy. DISCUSSION A multi-modal strategy incorporating optical character recognition and natural language processing may increase the number of cases identified while maintaining similar PPVs. Such algorithms, however, require that the needed information be embedded within clinical documents. CONCLUSION We have demonstrated that algorithms to identify and characterize cataracts can be developed utilizing data collected via the EHR. These algorithms provide a high level of accuracy even when implemented across multiple EHRs and institutional boundaries.

Knowledge-driven multi-locus analysis reveals gene-gene interactions influencing HDL cholesterol level in two independent EMR-linked biobanks.

Genome-wide association studies (GWAS) are routinely being used to examine the genetic contribution to complex human traits, such as high-density lipoprotein cholesterol (HDL-C). Although HDL-C levels are highly heritable (h2∼0.7), the genetic determinants identified through GWAS contribute to a small fraction of the variance in this trait. Reasons for this discrepancy may include rare variants, structural variants, gene-environment (GxE) interactions, and gene-gene (GxG) interactions. Clinical practice-based biobanks now allow investigators to address these challenges by conducting GWAS in the context of comprehensive electronic medical records (EMRs). Here we apply an EMR-based phenotyping approach, within the context of routine care, to replicate several known associations between HDL-C and previously characterized genetic variants: CETP (rs3764261, p = 1.22e-25), LIPC (rs11855284, p = 3.92e-14), LPL (rs12678919, p = 1.99e-7), and the APOA1/C3/A4/A5 locus (rs964184, p = 1.06e-5), all adjusted for age, gender, body mass index (BMI), and smoking status. By using a novel approach which censors data based on relevant co-morbidities and lipid modifying medications to construct a more rigorous HDL-C phenotype, we identified an association between HDL-C and TRIB1, a gene which previously resisted identification in studies with larger sample sizes. Through the application of additional analytical strategies incorporating biological knowledge, we further identified 11 significant GxG interaction models in our discovery cohort, 8 of which show evidence of replication in a second biobank cohort. The strongest predictive model included a pairwise interaction between LPL (which modulates the incorporation of triglyceride into HDL) and ABCA1 (which modulates the incorporation of free cholesterol into HDL). These results demonstrate that gene-gene interactions modulate complex human traits, including HDL cholesterol.

Adult supervision and pediatric injuries in the agricultural worksite

Appropriate supervision is recommended as a strategy to prevent pediatric farm injuries, yet virtually nothing is known about the quality of adult supervision on farms. We therefore explored the nature of adult supervision among pediatric farm injury cases using three theoretically relevant dimensions of supervision: (1) attention, (2) proximity, and (3) continuity. We examined a retrospective case series of 334 pediatric farm injury cases from Canada and the United States that resulted in death or required hospitalization. Patterns of supervision were coded according to the three dimensions. Approximately two-thirds of the injured children (231/334; 69%) had an adult supervisor available (attention). The supervisor was in close proximity of the child in only about half the cases (169/334; 51%) and it was even less common for the supervision to be continuous (37%). Thus, many injuries occurred when children were inadequately supervised. However, approximately one-third of the injured children (112/334; 34%) had what in other circumstances would be considered adequate adult supervision at the time of their injury event, defined theoretically as having supervision available, proximal, and continuous. Yet, children on farms were injured even in the presence of adequate adult supervision. These findings, along with a growing body of literature examining pediatric farm injuries, suggest a need to develop a new definition of adequate adult supervision within the context of the agricultural work environment, or to consider restricting the access of children, especially the very young, to this hazardous worksite.

Pediatric farm injuries involving non-working children injured by a farm work hazard: five priorities for primary prevention

Objectives: To describe pediatric farm injuries experienced by children who were not engaged in farm work, but were injured by a farm work hazard and to identify priorities for primary prevention. Design: Secondary analysis of data from a novel evaluation of an injury control resource using a retrospective case series. Data sources: Fatal, hospitalized, and restricted activity farm injuries from Canada and the United States. Subjects: Three hundred and seventy known non-work childhood injuries from a larger case series of 934 injury events covering the full spectrum of pediatric farm injuries. Methods: Recurrent injury patterns were described by child demographics, external cause of injury, and associated child activities. Factors contributing to pediatric farm injury were described. New priorities for primary prevention were identified. Results: The children involved were mainly resident members of farm families and 233/370 (63.0%) of the children were under the age of 7 years. Leading mechanisms of injury varied by data source but included: bystander and passenger runovers (fatalities); drowning (fatalities); machinery entanglements (hospitalizations); falls from heights (hospitalizations); and animal trauma (hospitalizations, restricted activity injuries). Common activities leading to injury included playing in the worksite (all data sources); being a bystander to or extra rider on farm machinery (all data sources); recreational horseback riding (restricted activity injuries). Five priorities for prevention programs are proposed. Conclusions: Substantial proportions of pediatric farm injuries are experienced by children who are not engaged in farm work. These injuries occur because farm children are often exposed to an occupational worksite with known hazards. Study findings could lead to more refined and focused pediatric farm injury prevention initiatives.

Cataract research using electronic health records

BackgroundThe eMERGE (electronic MEdical Records and Genomics) network, funded by the National Human Genome Research Institute, is a national consortium formed to develop, disseminate, and apply approaches to research that combine DNA biorepositories with electronic health record (EHR) systems for large-scale, high-throughput genetic research. Marshfield Clinic is one of five sites in the eMERGE network and primarily studied: 1) age-related cataract and 2) HDL-cholesterol levels. The purpose of this paper is to describe the approach to electronic evaluation of the epidemiology of cataract using the EHR for a large biobank and to assess previously identified epidemiologic risk factors in cases identified by electronic algorithms.MethodsElectronic algorithms were used to select individuals with cataracts in the Personalized Medicine Research Project database. These were analyzed for cataract prevalence, age at cataract, and previously identified risk factors.ResultsCataract diagnoses and surgeries, though not type of cataract, were successfully identified using electronic algorithms. Age specific prevalence of both cataract (22% compared to 17.2%) and cataract surgery (11% compared to 5.1%) were higher when compared to the Eye Diseases Prevalence Research Group. The risk factors of age, gender, diabetes, and steroid use were confirmed.ConclusionsUsing electronic health records can be a viable and efficient tool to identify cataracts for research. However, using retrospective data from this source can be confounded by historical limits on data availability, differences in the utilization of healthcare, and changes in exposures over time.

Evaluation of the North American Guidelines for Children’s Agricultural Tasks using a case series of injuries

Objective: To evaluate the potential for the North American Guidelines for Children’s Agricultural Tasks (NAGCAT) to prevent the occurrence of pediatric farm injuries. This evaluation focuses upon farm injuries experienced when children were engaged in farm work. Design: Novel outcome evaluation involving primary review of three retrospective case series. Setting: Fatal, hospitalized, and restricted activity injuries from the United States and Canada. Subjects: Nine hundred and thirty four pediatric farm injury cases. Methods: The applicability of NAGCAT to each case was rated. For injuries where NAGCAT were applicable, recurrent injury patterns were described and the potential for NAGCAT to prevent their occurrence was assessed. Results: A total of 283 (30.3%) cases involved children engaged in farm work. There was an applicable NAGCAT guideline in 64.9% of the work related cases. Leading individual guidelines applicable to the injury events were: (1) working with large animals; (2) driving a farm tractor; and (3) farm work with an all-terrain vehicle. In the judgment of the research team, 59.6% of these injuries were totally preventable if the principles espoused by NAGCAT had been applied. Conclusions: NAGCAT are a set of consensus guidelines aimed at the prevention of pediatric farm injuries. The findings suggest that NAGCAT, if applied, would be efficacious in preventing many of the most serious injuries experienced by children engaged in farm work. However, work related injuries represent only a modest portion of pediatric farm injuries. This new information assists in the refinement of NAGCAT as an injury control resource and puts its potential efficacy into context.

Characterization of Low-Density Lipoprotein Cholesterol-Lowering Efficacy for Atorvastatin in a Population-Based DNA Biorepository

The Marshfield Clinic Personalized Medicine Research Project (PMRP) represents a large population-based biobank located in central Wisconsin. To position the PMRP database for large-scale pharmacogenetic association studies in the context of lipid-lowering therapy, we constructed an electronic phenotyping algorithm to quantify exposure and dose-response for atorvastatin, the most commonly prescribed lipid-lowering agent within this population. The resulting datasets were used to generate five distinct parameters for atorvastatin-induced changes in low-density lipoprotein (LDL) cholesterol level: (i) pretreatment, baseline LDL level [E(0)]; (ii) absolute reduction in LDL; (iii) relative reduction in LDL; (iv) potency [ED(50)]; and (v) maximal efficacy [E(max)]. These parameters will facilitate the efficient application of electronic phenotyping for drug outcomes in the context of large pharmacogenetic association studies.

A genome-wide association study identifies variants in KCNIP4 associated with ACE inhibitor-induced cough.

The most common side effect of angiotensin-converting enzyme inhibitor (ACEi) drugs is cough. We conducted a genome-wide association study (GWAS) of ACEi-induced cough among 7080 subjects of diverse ancestries in the Electronic Medical Records and Genomics (eMERGE) network. Cases were subjects diagnosed with ACEi-induced cough. Controls were subjects with at least 6 months of ACEi use and no cough. A GWAS (1595 cases and 5485 controls) identified associations on chromosome 4 in an intron of KCNIP4. The strongest association was at rs145489027 (minor allele frequency=0.33, odds ratio (OR)=1.3 (95% confidence interval (CI): 1.2–1.4), P=1.0 × 10−8). Replication for six single-nucleotide polymorphisms (SNPs) in KCNIP4 was tested in a second eMERGE population (n=926) and in the Genetics of Diabetes Audit and Research in Tayside, Scotland (GoDARTS) cohort (n=4309). Replication was observed at rs7675300 (OR=1.32 (1.01–1.70), P=0.04) in eMERGE and at rs16870989 and rs1495509 (OR=1.15 (1.01–1.30), P=0.03 for both) in GoDARTS. The combined association at rs1495509 was significant (OR=1.23 (1.15–1.32), P=1.9 × 10−9). These results indicate that SNPs in KCNIP4 may modulate ACEi-induced cough risk.

The utility of BMD Z-score diagnostic thresholds for secondary causes of osteoporosis

SummaryThis very large dual X-ray absorptiometry (DXA) cohort confirmed a significant, inverse relationship between bone mineral density (BMD) Z-scores and the presence of secondary causes of osteoporosis but receiver operating characteristic (ROC) curves indicate that Z-score diagnostic thresholds (such as −2.0) discriminate poorly between the presence and absence of secondary causes of osteoporosis.IntroductionBMD Z-score diagnostic thresholds have been proposed to detect secondary causes of osteoporosis. To determine the sensitivity and diagnostic utility of such thresholds, we analyzed comprehensive BMD and personal health information data from a large, multispecialty group practice.MethodsAdult subjects were assigned their lowest axial BMD Z-score and ICD-9 diagnosis codes for secondary causes of osteoporosis when cited at least twice in their electronic medical record. Multiple logistic regression was used to model the prevalence of matching ICD-9 codes as a function of Z-score. ROC curves were used to investigate various Z-score cut points for sensitivity and specificity.ResultsEighteen thousand six hundred seventy-four subjects were analyzed. Secondary causes of osteoporosis were identified in 31% of men and 16% of women. The frequency of secondary causes varied with age and between genders and varied inversely with Z-score. No inflection point was observed in this relationship to suggest a useful clinical decision threshold. The difference in mean Z-score of those with and without a secondary cause of osteoporosis was biologically slight (±0.3). Low Z-score diagnostic thresholds were insensitive to the presence of secondary causes of osteoporosis and provided relatively poor predictive value.ConclusionsThis DXA cohort confirmed a significant inverse relationship between Z-score and the presence of secondary causes of osteoporosis but diagnostic Z-score thresholds discriminate poorly between the presence and absence of secondary causes of osteoporosis. If only patients with very low Z-scores are evaluated for secondary causes of osteoporosis the diagnostic specificity may be high but most cases will be missed.

Hearing conservation program for agricultural students: short-term outcomes from a cluster-randomized trial with planned long-term follow-up.

OBJECTIVES (1) To conduct a contemporary analysis of historical data on short-term efficacy of a 3-year hearing conservation program conducted from 1992 to 1996 in Wisconsin, USA, with 753 high school students actively involved in farm work; (2) to establish procedures for assessment of hearing loss for use in a recently funded follow-up of this same hearing conservation program cohort. METHODS We analyzed a pragmatic cluster-randomized controlled trial, with schools as the unit of randomization. Thirty-four rural schools were recruited and randomized to intervention or control. The intervention included classroom instruction, distribution of hearing protection devices, direct mailings, noise level assessments, and yearly audiometric testing. The control group received the audiometric testing. RESULTS Students exposed to the hearing conservation program reported more frequent use of hearing protection devices, but there was no evidence of reduced levels of noise-induced hearing loss (NIHL). CONCLUSION Our analysis suggests that, since NIHL is cumulative, a 3-year study was likely not long enough to evaluate the efficacy of this intervention. While improvements in reported use of hearing protection devices were noted, the lasting impact of these behaviors is unknown and the finding merits corroboration by longer term objective hearing tests. A follow-up study of the cohort has recently been started.