Electronic medical records for discovery research in rheumatoid arthritis

Authors


  • The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Library of Medicine or the NIH.

Abstract

Objective

Electronic medical records (EMRs) are a rich data source for discovery research but are underutilized due to the difficulty of extracting highly accurate clinical data. We assessed whether a classification algorithm incorporating narrative EMR data (typed physician notes) more accurately classifies subjects with rheumatoid arthritis (RA) compared with an algorithm using codified EMR data alone.

Methods

Subjects with ≥1 International Classification of Diseases, Ninth Revision RA code (714.xx) or who had anti–cyclic citrullinated peptide (anti-CCP) checked in the EMR of 2 large academic centers were included in an “RA Mart” (n = 29,432). For all 29,432 subjects, we extracted narrative (using natural language processing) and codified RA clinical information. In a training set of 96 RA and 404 non-RA cases from the RA Mart classified by medical record review, we used narrative and codified data to develop classification algorithms using logistic regression. These algorithms were applied to the entire RA Mart. We calculated and compared the positive predictive value (PPV) of these algorithms by reviewing the records of an additional 400 subjects classified as having RA by the algorithms.

Results

A complete algorithm (narrative and codified data) classified RA subjects with a significantly higher PPV of 94% than an algorithm with codified data alone (PPV of 88%). Characteristics of the RA cohort identified by the complete algorithm were comparable to existing RA cohorts (80% women, 63% anti-CCP positive, and 59% positive for erosions).

Conclusion

We demonstrate the ability to utilize complete EMR data to define an RA cohort with a PPV of 94%, which was superior to an algorithm using codified data alone.

INTRODUCTION

Electronic medical records (EMRs) used as part of routine clinical care have great potential to serve as a rich resource of data for clinical and translational research. There are 2 types of EMR data: “codified” (i.e., entered in a structured format) and “narrative” (i.e., free-form typed text in physician notes). Although the exact content will depend on an institution's EMR, codified EMR data often include basic information such as age, demographics, billing codes, and laboratory results. The content of narrative data, which often consist of typed information within physician notes, is usually broader in scope, providing information on a patient's chief symptom, other symptoms, comorbidities, medications, physical examination, and the physician's impression and plan (1). The ability to tap into this abundance of clinical information has widespread appeal, from biologists who link EMR to biospecimen data (2) to epidemiologists who link codified medical record data to outcomes of interest (3). However, EMR clinical data have been underutilized for discovery research because of concerns about data accuracy and validity.

Several studies have used codified EMR data, but not the complete EMR consisting of both narrative and codified data, to classify whether or not a patient has rheumatoid arthritis (RA) (3–7). In one study, at least 3 physician diagnoses of RA according to the International Classification of Diseases, Ninth Revision (ICD-9) were used to identify RA subjects, as this method resulted in RA estimates similar to population-based studies (8). A 1994 study from the Mayo Clinic found that computerized diagnostic codes for RA had a sensitivity of 89%, but a positive predictive value (PPV) of only 57% (4). In the Veterans Administration database, one ICD-9 code for RA was found to be 100% sensitive, but not very specific or accurate (specificity of 55%, PPV of 66%) (5). The addition of a prescription for a disease-modifying antirheumatic drug (DMARD) increased the PPV to 81%, but with a decrease in sensitivity to 85%. These rates of disease misclassification can have a profound impact on research studies that require precise disease definitions.

More recently, computational methods have been developed to extract clinical data entered in a typed format from the narrative EMR using a systematic approach. The conventional method of extracting narrative information for clinical research, which requires researchers to manually review charts, is labor intensive and inefficient. In contrast, natural language processing (NLP) represents an automated method of chart review by processing typed text into meaningful components based on a set of rules. To use NLP, a concept is defined that corresponds to a specific clinical variable of interest (e.g., radiographic erosions). Clinical experts developed lists of terms to be used for each NLP query. Terms for erosions might include: “presence of erosions on radiographs,” “erosions consistent with RA,” or “erosion positive.” NLP can also incorporate abbreviations (e.g., “erosion+”), misspellings (e.g., “radeograhic erosions”), and negation terms (e.g., “absence of erosions”). NLP has been applied to a limited number of biomedical settings, for example, mandatory reporting of notifiable diseases (9–11), definition of comorbid conditions (12–14) and medications (15, 16), and identification of adverse events (17, 18), but not yet for classification of diseases in an EMR.

In the current study, our objective was to classify RA subjects in our EMR with a high PPV. We assessed whether the combination of narrative EMR data (obtained using NLP) and codified EMR data (ICD-9 codes, medications, laboratory test results), together with robust analytical methods, can more accurately classify subjects with RA than the standard approach of using codified data alone.

MATERIALS AND METHODS

An overview of our approach is outlined in Figure 1. Starting with the complete EMR (narrative and codified data), we 1) created an RA database (RA Mart) of all possible RA patients; 2) randomly selected 500 subjects from the RA Mart for medical record review to develop a training set of RA and non-RA cases; 3) developed and trained 3 classification algorithms on the training set; 4) applied the 3 classification algorithms to the RA Mart to obtain the predicted RA cases; and 5) validated the classification algorithm by performing medical record reviews on 400 of the predicted RA cases (i.e., a validation set) to confirm RA status to determine the PPV. Steps 3–5 were conducted for each algorithm: narrative and codified EMR data (complete), codified EMR data, and narrative-only EMR data.

Figure 1.

Overview of the approach to classifying rheumatoid arthritis (RA) subjects in an electronic medical record (EMR). ICD-9 = International Classification of Diseases, Ninth Revision; anti-CCP = anti–cyclic citrullinated peptide.

Data source.

We studied the Partners HealthCare EMR, which is utilized by 2 large hospitals, Brigham and Women's Hospital and Massachusetts General Hospital, that combined care for approximately 4 million patients in the Boston, Massachusetts metropolitan area. The EMR began on October 1, 1996 for Brigham and Women's Hospital and October 3, 1994 for Massachusetts General Hospital. To build an initial database of potential RA subjects (RA Mart), we selected all subjects with ≥1 ICD-9 code for RA and related diseases (714.xx) or subjects who had been tested for antibodies to cyclic citrullinated peptide (anti-CCP) (Figure 1). Subjects who were deceased or age <18 years at the time of the RA Mart creation (June 5, 2008) were excluded. In total, 29,432 subjects had ≥1 ICD-9 code for RA (714.xx; n = 25,830) or had been tested for anti-CCP (n = 3,602; 4,283 subjects had ≥1 ICD-9 code for RA and had anti-CCP checked). The Partners Institutional Review Board approved all aspects of this study.

Codified EMR data.

We used the following codified data in our analysis: ICD-9 codes, electronic prescriptions, and anti-CCP and rheumatoid factor (RF) laboratory values. The ICD-9 codes included RA and related diseases (714.xx; excluding juvenile idiopathic arthritis/juvenile rheumatoid arthritis [JRA] codes), systemic lupus erythematosus (SLE; 710.0), psoriatic arthritis (PsA; 696), and JRA (714.3x). Because a single visit could result in multiple tests and notes, leading to multiple codes for the same day, we eliminated codes that occurred less than 1 week after a prior code. In our analysis, RA ICD-9 codes were analyzed in 2 forms: 1) number of RA ICD-9 codes for each subject at least 1 week apart (RA ICD-9), and 2) number of normalized RA ICD-9 codes, which is the natural log of the number of RA ICD-9 codes for each subject at least 1 week apart. We determined which subjects were RF and anti-CCP positive according to the cutoffs at each hospital laboratory. The presence of a coded medication signifies that a patient was prescribed the medication by a physician using a computerized prescription program embedded within our EMR or had the medication entered onto a medication list maintained by a physician. The presence of a coded medication does not signify that the medication was actually filled because patients can take prescriptions to any pharmacy. The coded medications assessed in this study included the DMARDs: methotrexate, azathioprine, leflunomide, sulfasalazine, hydroxychloroquine, penicillamine, cyclosporine, and gold. Biologic agents included the anti–tumor necrosis factor (anti-TNF) agents infliximab and etanercept, and other agents, including abatacept, rituximab, and anakinra. Adalimumab was not available as coded data in our system. To provide an index of medical care utilization, we assessed the number of “facts,” which is related to the number of medical entries a subject has in the EMR. Examples of a fact include: a physician visit, a visit to the laboratory for a blood draw, and a visit to radiology for a radiograph.

Narrative EMR data and NLP.

We used 5 types of notes to extract information from narrative data: health care provider notes, radiology reports, pathology reports, discharge summaries, and operative reports. We utilized NLP to extract clinical variables from the narrative data entered in a typed format (no scanned hand-written notes were used). We used the Health Information Text Extraction (HITEx) system (19) to extract the clinical information from narrative text. HITEx is an open-source NLP tool written in Java and built on the General Architecture for Text Engineering framework (20). The NLP application determines the structure of unstructured text records and outputs an annotated document tagging variables of interest (further details are provided by Zeng et al, 2006 [19]).

The variables included broad concept terms such as disease diagnoses (RA, SLE, PsA, and JRA), medications (listed above, with the addition of adalimumab), laboratory data (RF, anti-CCP, and the term “seropositive”), and radiology findings of erosions on radiographs. We used the HITEx system (19) to extract clinical information from narrative text. We extracted the variables mentioned above from the narrative data and created coded NLP variables for the number of mentions per subject as well as dichotomous variables for each disease diagnosis, medication, laboratory test result, and erosions on radiographs. To account for variability in language usage, a variety of specific phrases can be defined, which are then collapsed into a single concept term for analyses. The clinicians on the team developed lists of terms to be used for each NLP query. Further analysis was performed to determine positive or negative variables. For example, a patient was flagged as being CCP positive by NLP if terms were found in their records such as “anti-CCP+” and “CCP positive RA.” For RF, anti-CCP, seropositive, and erosions, a negation-finding algorithm was used to distinguish subjects who were positive or negative for the variable. For example, the algorithm could distinguish a subject who was anti-CCP positive versus anti-CCP negative.

Two reviewers (KPL and RMP) assessed the precision of select NLP concepts: anti-CCP positive, RF positive, seropositive, methotrexate, and etanercept. For each concept, one sentence containing the concept was selected from each of 150 randomly selected subjects with records containing the concept. The reviewers assessed whether the concept extraction was correctly described in the context of the sentence. We assessed 2 categories of NLP concepts. The first assessment for precision identifies whether a concept was identified appropriately from the physician note within a specific sentence. Concepts in this group include disease diagnoses and medications. A patient was scored as “correct” for methotrexate by NLP if the term methotrexate was present in the sentence extracted from the medical record. This includes instances where subjects were prescribed the medication, the medication was held, the medication was contemplated, or if the subject had taken the medication in the past. The second assessment for precision required that the patient have a positive result. This pertains to the concepts RF, anti-CCP, seropositive, and erosions. We scored the NLP as correct for “RF positive” only if the patient was also found to be RF positive on review from the sentence extracted from the medical record. We scored NLP as incorrect if RF was mentioned with no evidence that the patient was RF positive in the sentence. An example of how precision (with respect to PPV) was calculated is as follows: Precision = number of sentences RF positive by NLP and confirmed as RF positive on review/number of sentences RF positive by NLP. The precision of NLP concepts was high: erosions 88% (95% confidence interval [95% CI] 84–91%), seropositive 96% (95% CI 95–97%), CCP positive 98.7% (95% CI 98–99%), RF positive 99.3% (95% CI 99.1–99.4%), methotrexate 100%, and etanercept 100%.

Training set of 500 subjects.

We established a training set of 500 subjects randomly selected from the RA Mart for medical record review. To establish the gold standard diagnosis, 2 rheumatologists (KPL and RMP) reviewed the medical records for the presence of the 1987 American College of Rheumatology (ACR; formerly the American Rheumatism Association) classification criteria for RA (21) and classified subjects as definite RA, possible/probable RA, and not RA. Definite RA was defined as subjects who had a rheumatologist's diagnosis of RA and supporting clinical data such as records describing synovitis, erosions, or >1 hour of morning stiffness. Possible RA was defined as subjects with persistent inflammatory arthritis with RA in the differential diagnosis by a physician. Subjects with a diagnosis of RA by a physician, but with insufficient supporting information of clinical signs and symptoms of the disease, were also classified as possible RA. Finally, subjects with an alternate rheumatologic diagnosis or whose diagnosis was unclear were considered not to have RA.

For our training set, subjects classified as definite RA were considered “RA cases,” whereas subjects classified as possible and as not having RA were classified as “controls.” Eighty-one percent of RA cases had sufficient information from the EMR to fulfill the 1987 ACR classification criteria for RA (21). This is consistent with the published specificity of the 1987 ACR criteria, which ranges from 80–90% when compared with the gold standard of a rheumatologist's diagnosis of RA (21, 22). Two authors (KPL and RMP) reviewed the same 20 subjects to assess percent agreement, and were in 100% agreement on the final diagnosis.

Classification algorithm: selecting informative variables and assigning parameters.

We used penalized logistic regression to develop a classification algorithm to predict the probability of having RA (23, 24). To avoid overfitting the model, we used the adaptive lasso procedure, which simultaneously identifies influential variables and provides stable estimates of the model parameters (25). The optimal penalty parameter was determined based on the Bayesian information criterion. We developed 3 different algorithms using 1) codified EMR variables only, 2) narrative EMR variables only, and 3) complete variables (narrative and codified). All 3 models were adjusted for age and sex, and all of the predictors were standardized to have unit variance. The predicted probabilities based on these models were used to classify subjects as having RA.

We selected the threshold probability value for classifying RA by setting the specificity level at 97% for all 3 algorithms. Subjects whose predicted probability exceeded the threshold value were classified as having RA, denoted by Alg. To assess the overall accuracy of these algorithms in classifying RA with the training data and to estimate the threshold value for Alg, we used 3-fold cross-validation repeated 50 times to correct for potential overfitting bias. Furthermore, we used the bootstrap method to estimate the standard error and obtain confidence intervals for the accuracy measures. The predictive accuracy of the algorithm to classify RA versus non-RA was subsequently validated using a separate validation set.

Validation of the classification algorithm and assessment of sensitivity, specificity, and PPV.

Once the classification algorithm was established, we applied it to the remaining RA Mart and assigned a probability of RA to each subject. To validate the performance of the classification algorithm, we randomly sampled an independent set of 400 subjects (validation set) from the subset of subjects who were classified as having RA (Alg by any of the 3 algorithms). These cases were then validated through a blinded medical record review for RA by 2 rheumatologists (KPL and RMP). The PPV, sensitivity, and specificity were calculated using the following formulas: PPV = number of Alg subjects confirmed as having RA on medical record review/number of Alg subjects; sensitivity = (PPV × PAlg)/PRA; and specificity = 1 − [((1 − PPV) × PAlg)/(1 − PRA)], where PAlg = the proportion of subjects identified by the algorithm as having RA in the RA Mart and PRA = the RA prevalence estimated from the training set. Sampling the validation set from the subset of subjects who were classified as having RA can improve the precision in estimating the PPV, which is the primary accuracy parameter and outcome of interest.

To assess and compare the difference in accuracy between the 3 algorithms, we compared their PPVs and obtained confidence intervals using the validation data: difference in PPV = PPV complete algorithm − PPV codified variables–only algorithm; and difference in PPV = PPV complete algorithm − PPV narrative variables–only algorithm.

The differences in PPVs were significant if the 95% CI did not include zero. Although the PPVs between the 3 algorithms can be compared, the 95% CIs associated with the PPVs (in contrast to the difference in PPVs) cannot because these estimates were derived from the same validation set of 400 subjects for all 3 algorithms.

For comparison, we also assessed the accuracy of the criteria used in administrative database studies: ≥3 ICD-9 codes for RA (8) and ≥1 RA ICD-9 code plus ≥1 DMARD (5). We used the training set to generate these data because it allows for unbiased estimates of these simple criteria. To compare differences in accuracy between our algorithms and the simple criteria above, we also used the difference in PPV and 95% CI.

Descriptive statistics.

We assessed differences in characteristics between RA cases and controls in the training set using the t-test and the Wilcoxon's rank sum test to compare differences between means and medians, respectively. P values are 2-sided. The chi-square test was used for between-group comparisons expressed as proportions, and analysis of variance was used for comparison of multiple groups.

Case-only analysis.

To assess whether our EMR RA cohort could replicate known associations among clinical variables, we performed a case-only analysis to compare the risk of erosions in anti-CCP–positive versus anti-CCP–negative subjects and RF-positive versus RF-negative subjects. We assessed the association between anti-CCP and radiographic erosions by including only those subjects in our database who have had anti-CCP tested in the clinical laboratory (i.e., autoantibody status was derived from codified data). Similarly, we assessed the relationship between RF and erosions only among those who had RF tested. Odds ratios (ORs) and 95% CIs were calculated using 2 × 2 contingency tables. All analyses were conducted with SAS software, version 9.2 (SAS Institute), and the R package (The R project for Statistical Computing, online at: http://www.r-project.org/).

RESULTS

Classification algorithm.

An overview of our approach is shown in Figure 1. Of 500 subjects sampled from the RA Mart (training set), 96 subjects (19%) with a single ICD-9 code for RA were determined to have a diagnosis of RA by medical record review; the remaining 404 subjects had either possible RA (n = 84) or no evidence of RA (n = 320). The clinical characteristics extracted from the codified compared with the narrative EMR data are shown in Tables 1 and 2 for the 500 subjects in our training set. There was a strong correlation between identification as an RA case on medical record review and having a higher number of RA ICD-9 codes and a higher number of NLP mentions of RA (P < 0.0001). Methotrexate was the most common medication prescribed for RA cases (34% in the codified EMR data) and was also the most commonly mentioned medication in the text notes (81% in the narrative EMR data).

Table 1. Characteristics of the training set (n = 500)*
 RA casesControlsP
  • *

    Values are the number (percentage) unless otherwise indicated. RA = rheumatoid arthritis; IQR = interquartile range; ACR = American College of Rheumatology.

  • Subjects with possible and no RA.

Total96 (19)404 (81) 
Age, mean ± SD years60.4 ± 1656.1 ± 190.04
Women74 (77)300 (74)0.6
Race  0.0003
 White64 (67)286 (71) 
 African American3 (3.1)46 (11) 
 Other7 (7.3)36 (8.9) 
 Unknown22 (23)36 (8.9) 
No. of facts, median (IQR)750 (2,159)952 (1,722)0.5
Rheumatologist-diagnosed RA95 (99)21 (5.3)< 0.0001
Fulfills ACR criteria77 (80)9 (2.2)< 0.0001
Table 2. Comparison of the distribution of codified compared with narrative data extracted using natural language processing in the training set (n = 500)*
 Codified dataNarrative data
RA casesControlsPRA casesControlsP
  • *

    Values are the number (percentage) unless otherwise indicated. RA = rheumatoid arthritis; PsA = psoriatic arthritis; SLE = systemic lupus erythematosus; JRA = juvenile rheumatoid arthritis; MTX = methotrexate; anti-TNF = anti–tumor necrosis factor; CCP = cyclic citrullinated peptide; RF = rheumatoid factor; NA = not applicable.

  • Subjects with possible and no RA.

  • In codified data: RF or anti-CCP positive; in narrative data: the term “seropositive.”

Total96 (19)404 (81) 96 (19)404 (81) 
Disease codes per subject, median (range)
 RA codes11 (141)1 (60)< 0.000110 (111)0 (77)< 0.0001
 PsA codes0 (1)0 (110)0.20 (3)0 (137)0.18
 SLE codes0 (9)0 (67)0.0070 (13)0 (115)0.007
 JRA codes0 (4)0 (39)0.820 (15)0 (60)0.55
Medications
 MTX33 (34)39 (9.7)< 0.000178 (81)100 (25)< 0.0001
 Anti-TNF30 (31)20 (5.0)< 0.000147 (49)47 (12)< 0.0001
Autoantibody studies
 CCP positive19 (20)8 (2.0)< 0.000115 (16)7 (1.7)< 0.0001
 RF positive43 (45)115 (28)0.002133 (34)36 (8.9)< 0.0001
 Seropositive45 (47)116 (29)< 0.000131 (32)7 (1.7)< 0.0001
Radiology
 ErosionsNANANA42 (44)35 (8.7)< 0.0001

To select the most informative variables that differentiate the RA cases from the controls in our training set, we used a statistical method based on penalized logistic regression. This method identified 14 variables for the narrative and codified (complete) classification algorithm, shown in Table 3 in order of predictive value. The features selected for the codified EMR variables–only algorithm, in order of predictive value, included ICD-9 RA, normalized ICD-9 RA, anti-TNF, RF positive, and methotrexate for positive predictors, and ICD-9 JRA, ICD-9 SLE, and ICD-9 PsA for negative predictors. The features selected for the narrative (NLP) EMR variables only–algorithm included RA, seropositive, anti-TNF, positive erosions, methotrexate, CCP positive, other DMARDs, and age for positive predictors, and SLE, PsA, and JRA for negative predictors.

Table 3. Variables selected for the complete algorithm (narrative and codified EMR data) from the logistic regression in order of predictive value*
VariableStandardized regression coefficientStandard error
  • *

    EMR = electronic medical record; NLP = natural language processing; RA = rheumatoid arthritis; ICD-9 = International Classification of Diseases, Ninth Revision; RF = rheumatoid factor; anti-TNF = anti–tumor necrosis factor; anti-CCP = anti–cyclic citrullinated peptide; DMARDs = disease-modifying antirheumatic drugs; JRA = juvenile rheumatoid arthritis; SLE = systemic lupus erythematosus; PsA = psoriatic arthritis.

  • ICD-9 RA normalized = ln (no. of ICD-9 RA codes per subject ≥1 week apart).

  • Codified anti-TNF = etanercept and infliximab (adalimumab was not available in our EMR).

  • §

    NLP anti-TNF = adalimumab, etanercept, and infliximab.

Positive predictors
 NLP RA1.110.48
 NLP seropositive0.740.26
 ICD-9 RA normalized0.710.23
 ICD-9 RA0.660.44
 NLP erosions0.460.29
 Codified RF negative0.360.36
 NLP methotrexate0.30.34
 Codified anti-TNF0.290.3
 NLP anti-CCP positive0.270.25
 NLP anti-TNF§0.20.36
 NLP other DMARDs0.130.34
Negative predictors
 ICD-9 JRA−0.980.9
 ICD-9 SLE−0.571.09
 NLP PsA−0.510.74

We applied the 3 algorithms to the entire RA Mart of 29,432 subjects (excluding the 500 subjects from the training set). The narrative and codified (complete) classification algorithm classified 3,585 subjects as having RA (Table 4). The codified-only and narrative-only algorithms classified 3,046 and 3,341 subjects, respectively, as having RA.

Table 4. Comparison of performance characteristics from validation of the complete classification algorithm (narrative and codified) with algorithms containing codified-only and narrative-only data*
ModelRA by algorithm or criteria, no.PPV (95% CI), %Sensitivity (95% CI), %Difference in PPV (95% CI), %
  • *

    The complete classification algorithm was also compared with criteria for RA used in published administrative database studies. RA = rheumatoid arthritis; PPV = positive predictive value; 95% CI = 95% confidence interval; NLP = natural language processing; ICD-9 = International Classification of Diseases, Ninth Revision; DMARD = disease-modifying antirheumatic drug.

  • Difference in PPV = PPV of complete algorithm − comparison algorithm or criteria.

  • Significant difference in PPV compared with the complete algorithm.

Algorithms
 Narrative and codified (complete)3,58594 (91–96)63 (51–75)Reference
 Codified only3,04688 (84–92)51 (42–60)6 (2–9)
 NLP only3,34189 (86–93)56 (46–66)5 (1–8)
Published administrative codified criteria
 ≥3 ICD-9 RA codes7,96056 (47–64)80 (72–88)38 (29–47)
 ≥1 ICD-9 RA codes plus ≥1 DMARD7,79945 (37–53)66 (57–76)49 (40–57)

Validation of the classification algorithm.

The narrative and codified (complete) classification algorithm performed significantly better than algorithms using either codified or narrative data alone (Table 4). There was a 6% (95% CI 2–9%) difference in PPV between the complete algorithm compared with the codified-only algorithm, and a 5% (95% CI 1–8%) difference in PPV between the complete algorithm and the narrative-only algorithm. The estimated sensitivities were also lower in the codified-only and narrative-only algorithms (51% and 56%, respectively, compared with 63% for the complete algorithm). Examples of the diagnoses of the subjects misclassified in the complete algorithm were erosive osteoarthritis, PsA, a “spondylitic variant,” and “right knee monarthritis.”

We also applied criteria used in administrative database studies for comparison: ≥3 ICD-9 codes for RA (8) and ≥1 RA ICD-9 code plus ≥1 DMARD (5) (Table 4). The PPV of the former was 56% (95% CI 47–64%) and the latter was 45% (95% CI 37–53%). Using the complete classification algorithm resulted in an increase in PPV of 38% (95% CI 29–47%) when compared with ≥3 RA ICD-9 codes, and an increase in PPV of 49% (95% CI 40–57%) when compared with ≥1 RA ICD-9 code plus ≥1 DMARD.

We used the PPV estimates to determine the increase in the total number of RA subjects classified by our 3 algorithms. The complete algorithm with a PPV of 94% would identify 3,370 RA subjects, the codified data–only algorithm with a PPV of 88% would identify 2,680 RA subjects, and a narrative data–only algorithm would identify 2,973 RA subjects. This represents a 26% increase in the identification of true RA subjects if the complete algorithm was used compared with the codified-only algorithm.

Clinical characteristics of the EMR RA cohort.

We assessed the clinical characteristics of the 3,585 subjects classified as having RA (EMR cohort). The clinical characteristics of our EMR cohort were similar to published data from the Consortium of Rheumatology Researchers of North America (26), an independent cohort of RA subjects assembled through traditional patient recruitment (Table 5).

Table 5. Characteristics of patients classified as having rheumatoid arthritis by the complete classification algorithm from our EMR compared with published data from CORRONA*
CharacteristicsEMR cohort (n = 3,585)CORRONA (n = 7,971)
  • *

    Values are the percentage unless otherwise indicated. EMR = electronic medical record; CORRONA = Consortium of Rheumatology Researchers of North America; anti-CCP = anti–cyclic citrullinated peptide; N/A = not applicable; RF = rheumatoid factor; MTX = methotrexate; anti-TNF = anti–tumor necrosis factor.

Age, mean ± SD57.5 ± 17.558.9 ± 13.4
Women79.974.5
Anti-CCP positive63N/A
RF positive74.472.1
Erosions59.259.7
MTX59.552.8
Anti-TNF32.622.6

We also assessed whether we could reproduce known associations between clinical features within our EMR cohort. Consistent with previous reports, we found that anti-CCP–positive subjects (defined using codified EMR data) have an elevated risk of erosions (defined using NLP from narrative data) compared with anti-CCP–negative subjects (OR 1.5, 95% CI 1.2–1.9) (27). We observed a similar relationship when RF-positive subjects were compared with RF-negative subjects (OR 1.3, 95% CI 1.1–1.6). The trend toward a higher risk of erosions in RA subjects seen in anti-CCP–positive subjects compared with those who are RF positive is consistent with those seen in the published literature (28, 29).

DISCUSSION

With the increasing adoption of EMRs (30, 31) and the high cost of maintaining large cohort studies, harnessing the complete EMR (narrative and codified data) for use in biomedical research offers an untapped resource for clinical and translational research. We have demonstrated that it is possible to accurately identify a cohort of RA subjects within an EMR with characteristics comparable with those of large cohort studies recruited using conventional methods. This represents a novel approach for establishing large patient registries in a high-throughput and cost-effective manner.

A major criticism of EMR data is accuracy. In our study, we provide convincing evidence that complete EMR data (narrative and codified data), together with robust analytical methods, can be used to identify subjects with RA with a high PPV of 94% for the complete algorithm. There was a significant increase in the PPV of 6% when narrative data were included in an algorithm containing only codified data. This degree of accuracy is substantially higher than previous studies that used EMR data (5). In our study, the PPV of a single ICD-9 code was only 19% (prevalence of RA in the training set). Published studies using a combination of codified data only had lower PPVs when applied to our data set; ≥3 ICD-9 codes for RA (8) had a PPV of 56%, and ≥1 RA ICD-9 code plus ≥1 DMARD (5) had a PPV of 45% in our data set. Moreover, incorporation of narrative data into a classification algorithm containing codified data not only increased the PPV, but also the sensitivity, thereby increasing the sample size by 26%. The increase in PPV and sample size can have a profound impact on the power of the study, particularly those requiring precise disease phenotypes.

There are at least two reasons why our approach outperformed previous methods. First, we used NLP to incorporate the narrative EMR data into our classification algorithm. Narrative EMR data are increasingly accessible, with an estimated 20–30% of physicians maintaining electronic notes on their subjects (31–33). In our RA Mart, some clinical data were available in narrative notes but not in the codified EMR (e.g., radiographic erosions), and some clinical data were more detailed in the narrative notes than in the codified EMR data. For example, codified data for methotrexate are present only if it was prescribed, whereas narrative methotrexate data were available if a subject was receiving methotrexate, if it was taken in the past, or if it was considered. Second, we developed a robust algorithm that selected the most informative variables from an expanded list of potential clinical variables. We did not rely on a prespecified set of rules to categorize subjects, as is often used in administrative database studies. In our complete model, using both narrative and codified EMR data, the selected variables were quite diverse, including diagnostic codes for RA (NLP for RA and codified ICD-9 codes for RA), concurrent medication (NLP for methotrexate), absence of diseases that mimic RA (SLE, JRA, and PsA), and presence of RA-specific autoantibodies. This technique using a multivariable model can result in a counterintuitive direction of influence for a particular variable due to colinearity; in our model using both codified and NLP data, the codified RF-negative variable had a positive influence on selecting RA subjects. This was likely due to colinearity of the codified RF-negative variable with the NLP anti-CCP–positive variable. Overall, it is the combined influence of all of the variables in the model that is important for the prediction of RA. In the algorithm using codified data alone, RF positive had a positive influence and RF negative was not included in the model.

An exciting prospect is the implementation of our approach in EMRs at other institutions to demonstrate the portability of our EMR algorithm to classify RA patients. The tools and techniques utilized in building our EMR database, such as the program used for NLP, are open source and are freely available to the rheumatology community (online at: www.i2b2.org). Similarly, institutions with primarily codified EMR data can implement our codified-only EMR algorithm (sensitivity of 51%, PPV of 88%). Institution-specific expertise from clinicians, statisticians, and bioinformaticians would be required to optimize the performance of any EMR algorithm.

Increasingly, efforts have been made to link EMR data to biospecimen repositories (2). At our institution (Partners HealthCare), a concerted effort has been made to link discarded blood samples to EMR data, thereby enabling serologic and genetic studies (34). Once this infrastructure is in place, collection of biospecimens is affordable on a large scale (and across multiple diseases). A similar infrastructure at other institutions would create a large national RA registry with access to biospecimens linked to detailed EMR clinical data.

An important limitation of conducting studies based in EMRs is access to only clinical data that are collected as part of routine patient care at the institution(s). For our study, we used an EMR with comprehensive outcomes and clinical information for subjects who obtained care at 2 tertiary care academic medical centers; other centers may have more limited EMR clinical data. Without additional institutional review board approval, we cannot recontact subjects to employ detailed questionnaires on exposures or other clinical variables.

In conclusion, creating clinical research databases from an EMR is an efficient and powerful tool for clinical and translational research. If successfully implemented across multiple institutions, it is theoretically possible to establish large patient registries with detailed clinical outcome data, where each institution could maintain local control of confidential patient clinical data. Biomedical research, and ultimately patients with RA, have much to gain by utilization of EMRs for discovery research.

AUTHOR CONTRIBUTIONS

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be submitted for publication. Dr. Plenge had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. Liao, Cai, Raychaudhuri, Churchill, Karlson, Plenge.

Acquisition of data. Gainer, Goryachev, Raychaudhuri, Murphy, Kohane, Karlson, Plenge.

Analysis and interpretation of data. Cai, Zeng-Treitler, Szolovits, Murphy, Karlson, Plenge.

Acknowledgements

The authors would like to thank the Partners Research Patient Database Registry.

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