Studies of carotid endarterectomy (CEA) require stratification by symptomatic vs asymptomatic status because of marked differences in benefits and harms. In administrative datasets, this classification has been done using hospital discharge diagnosis codes of uncertain accuracy. This study aims to develop and evaluate algorithms for classifying symptomatic status using hospital discharge and physician claims data.
Methods
A single center’s administrative database was used to assemble a retrospective cohort of participants with CEA. Symptomatic status was ascertained by chart review prior to linkage with physician claims and hospital discharge data. Accuracy of rule-based classification by discharge diagnosis codes was measured by sensitivity and specificity. Elastic net logistic regression and random forest models combining physician claims and discharge data were generated from the training set and assessed in a test set of final year participants. Models were compared to rule-based classification using sensitivity at fixed specificity.
Results
We identified 971 participants undergoing CEA at the Vancouver General Hospital (Vancouver, Canada) between January 1, 2008 and December 31, 2016. Of these, 729 met inclusion/exclusion criteria (n = 615 training, n = 114 test). Classification of symptomatic status using hospital discharge diagnosis codes was 32.8% (95% CI 29–37%) sensitive and 98.6% specific (96–100%). At matched 98.6% specificity, models that incorporated physician claims data were significantly more sensitive: elastic net 69.4% (59–82%) and random forest 78.8% (69–88%).
Conclusion
Discharge diagnoses were specific but insensitive for the classification of CEA symptomatic status. Elastic net and random forest machine learning algorithms that included physician claims data were sensitive and specific, and are likely an improvement over current state of classification by discharge diagnosis alone.
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Abkürzungen
CEA
Carotid endarterectomy
ICD
International Classification of Diseases
ROC
Receiver operating characteristic curve
AUC
Area under curve (in this context, area under the receiver operating characteristic curve)
LOESS
Locally-estimated scatterplot smoothing
Introduction
Historical evidence supports asymptomatic [1] (primary prevention) and symptomatic [2] (secondary prevention) indications for carotid endarterectomy (CEA), but there is equipoise for the benefit of asymptomatic intervention in the context of contemporary medical therapy [3]. If the ongoing CREST-2 study [4] fails to demonstrate the benefit of primary prevention CEA beyond medical therapy, then studies of the appropriate use of CEA by symptomatic status are expected to follow. Administrative data is likely to be used for these studies, given its low cost and population-level scope. Whether these studies will be valid will entirely depend on the accuracy of administrative data for classifying CEA symptomatic status. Classification of symptomatic status is also critical for the construction of administrative data indicators for CEA quality, including: (1) timeliness: a widely-accepted two-week time target is applicable only to secondary prevention [2] and (2) safety: acceptable rates of peri-operative morbidity and mortality for primary prevention are lower than rates acceptable for secondary prevention [5].
Using a systematic search strategy, we identified studies that used administrative data to classify the symptomatic status of patients who had undergone CEA (Supplementary Table 1). All studies identified by our search classified patients by rule using hospital discharge diagnosis. Only one group studied the performance of this classification relative to a gold standard chart review population, determining sensitivity 36.6% and specificity 93.1% [6]. Consistent with an insensitive measure, the rates for symptomatic intervention were generally much lower in administrative-data based cohorts (2.7–30.1%) [6‐28] than in comparable registry cohorts relying on manual classification (CEA 30.7–43.5%) [28‐32]. Rule-based classification by discharge diagnosis will likely yield ‘asymptomatic’ cohorts with many symptomatic patients, threatening the validity of studies that use this technique.
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In this study, we aimed to improve upon the current rule-based method for classifying CEA symptomatic status by: 1) augmenting discharge data with physician claims data, and 2) using elastic net logistic regression and random forest machine learning (ML) models. We developed our models using a cohort of patients undergoing CEA at a major tertiary center in Vancouver, Canada between 2008 and 2015, and validated them in a cohort undergoing CEA at the same institution in 2016.
Method
Study setting and cohort
The setting of the study was the Vancouver General Hospital, a quaternary centre with a mixed catchment of local urban and rural/remote referral populations. We defined our study cohort by querying our institution’s hospital discharge database for carotid revascularization codes (Canadian Classification of Interventions 1.JE.57, 1.JE.50, 1.JE.87) [23] between January 1, 2008 and December 31, 2016. For participants with multiple procedures during this time, only the earliest was included. We identified very few instances of carotid stenting, so these patients were excluded from our cohort. Other exclusion criteria included: indication unrelated to atherosclerotic secondary prevention, symptomatic status not documented, symptom onset outside of province, symptom onset in hospital, stroke as complication of procedure, or initial treatment with medical therapy (Supplementary Fig. 1).
Data sources
Participants were linked with population-level datasets for physician claims (Medical Services Plan Payment Information File [33] and Consolidation File [34]), hospital discharges (Discharge Abstract Database [35]) and demographics. These are available as by-products of the setting’s single-payer healthcare system, with near-universal population coverage. An anonymized dataset was created for analyses. Raw data were accessible to the investigators. The data that support the findings of this study are available from Population Data BC, but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of Population Data BC.
Data preparation
Claims and hospital discharges were trimmed to a window of 6 months pre-surgery (by definition, symptomatic status refers to events that happened within 6 months of surgery [2], and we did not wish to add noise from possible earlier events) and 7 days post-procedure (to reduce risk of excluding relevant physician claims based on claim date error). Duplicate physician claims, generated through the billing adjudication process, were removed. Physician claims diagnoses (ICD-9) were truncated at three characters, as per previously published methods [36]. All test set participants were allocated from the final year of data to maximize similarity to future data [37].
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Discharge variables
All ICD-9-CM diagnostic codes used in previous studies [6‐28] were mapped to their ICD-10-CA equivalents, which was the discharge coding standard used throughout our study period (Table 1). We additionally examined all I6X diagnostic codes present in our dataset to ensure that no relevant diagnoses were missed. Other discharge variables included age, sex, in-metro residence, and admission type (emergent, urgent, or elective).
Table 1
Diagnosis cluster definitions for ICD-9 and ICD-10-CA
Diagnosis cluster
ICD-10-CA (5-character code)
ICD-9 (3-digit code)
Ischemic stroke
I63.X (except I63.6, venous thrombosis), I64 (stroke not specified as hemorrhage or infarction), I66.0–2,4,8–9 (cerebral arterial stenosis or occlusion without infarction; included even though these codes specifically exclude infarction)
434 (some codes exclude infarction, but these are rarely used in BC), 436 (acute cerebrovascular disease), 438 (late effects of cerebrovascular disease)
781 (neurological symptoms), 341 (demyelinating symptom, but frequently used in our sample). Omit 784 (embeds speech in context of ‘head and neck’)
Stenosis (asymptomatic)
I65.2, I65.3, I65.9 (stenosis of carotid or multiple arteries)
433 (some codes include infarction, but these are rarely used in BC)
Physician claims variables
Claims data were used to create diagnosis and service variables. Diagnoses were defined by 3-character ICD-9 codes, which was the coding standard for physician claims used throughout the study period (in contrast to discharge ICD-10 coding). Reasoning that the predictive value of a diagnosis might vary depending on the person making it, we pre-specified select diagnosis by specialty combinations (e.g. TIA by neurologist vs. non-neurologist (Supplementary Table 2). Based on clinical experience, we expected that symptomatic patients would undergo symptom-specific evaluation, such as a CT head for a new central nervous system symptom, and that this would be reflected in claimed services. We believed that the occurrence of these services would likely prove to be reliable signals for symptomatic events. Services were defined by 5-character fee item codes, which were clustered into categories based on descriptions in the physician payment schedule (Supplementary Table 3).
We used a 4-step workflow to transform the many-to-one raw data into a one-to-one analytical dataset: (1) clustering – grouping similar service or diagnosis items together, such as ICD-9362 retinal disorders and 368 visual disturbance, (2) reduction – removing conceptual duplicates, such as the same diagnosis made by the same provider on different days, (3) weighting – assigning a value based on time from CEA, and (4) summarizing – collapsing data into a single row as either the sum or maximum value (Supplementary Fig. 2 presents a step-by-step illustration of these terms in the context of our data).
Missing values
Given the original dataset, missing values in predictor data are not possible (conditions are either observed or not observed). Median imputation was used for participants missing symptom type (N = 6), which was used only to describe the study population.
Outcome definitions
The gold standard for this study was symptomatic status as assessed by chart review (SVG, AA). Consultations, operative notes, and discharge summaries within 6 months of the intervention were reviewed. Interrater agreement for symptomatic status was measured using the Kappa statistic for two raters. Interrater conflicts were subsequently resolved by consensus.
Comparison of model discrimination
The ML models used in this analysis yield continuous probability values, which can be easily used in receiver-operating characteristic curve (ROC) analysis for the measurement of discrimination. However, the rule-based diagnosis method yields a single binary class, which cannot be used in ROC analysis. As an alternative, for each ML model we calculated confidence intervals for sensitivity at a fixed specificity matching the specificity of the rule-based method. Specifically, if the ML model’s 95% CI for sensitivity excluded the measured sensitivity of the rule-based method, at the same margin of specificity, we took this as evidence for superior discrimination of the ML model. We believe that this sets up a reasonable like-to-like comparison between binary and continuous classifier types. In contrast, because all ML models generate continuous output, ML models are compared to each other using the area under the ROC curve (AUC).
Sample size
Sensitivity is a binomial proportion, so the necessary sample size can be estimated by calculating the confidence interval of a comparison value [38]. As long as the true sensitivity of the comparison test is 0.6 or greater, a test set of n = 75 participants (25 cases / 50 controls) will have more than 95% power to exclude the previously reported sensitivity of 36% [6]. Assuming a test set of no larger than 25% of the total, a minimum of n = 300 participants is required.
Models
We specified a set of five models of increasing complexity: (1) RuleDX: rule-based classification by hospital discharge diagnosis alone (current state method), (2) LogisticHOSP: elastic net logistic using hospital discharge variables, (3) LogisticDX: elastic net logistic adding physician claims diagnoses to hospital discharge variables, (4) LogisticALL elastic net logistic using all variables, and (5) ForestALL: random forest using all variables. Elastic net and random forest models were selected because they incorporate automated variable selection, require a modest amount of data for training (e.g. in contrast to neural network) and include variable importance metrics for model interpretation. Random forest models are additionally advantaged by the automatic incorporation of interactions, whereas elastic net models are advantaged by linear relationships (random forest are binary).
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Models were built and analyzed using a 4-step workflow: (1) model specification tuning using training set 10-fold 3-repeat cross-validation, (2) model performance assessment using training set 10-fold 10-repeat cross-validation, (3) final model fitting using the complete training set, and (4) final model performance measurement using 2000 bootstrapped test set samples.
Model specifications were tuned using the tidymodels implementation of Bayesian grid search [39], using default values except where noted. Elastic net logistic regression models were built using glmnet [40], with tuning of mixture and penalty (controlling variable selection and overfitting control). Random forest models were built using ranger [41], with tuning of the number of variables randomly sampled as candidates at each split (specified range 2–20), minimum node size, and tree number (all controlling the complexity of the resulting algorithm).
Sensitivity and AUC
Exact binomial confidence intervals for the sensitivity and specificity of RuleDX were calculated using the combined test and training sets. To permit like-to-like comparison between the diagnosis only and ML methods, the sensitivity of ML models was assessed at the specificity observed for RuleDX. Training set sensitivity and AUC were calculated using cross-fold hold-outs, yielding mean and standard error. Test set sensitivity and AUC were assessed via bootstrapped empirical 95% confidence intervals.
Calibration
Calibration was assessed was assessed by plot within the test set using LOESS-smoothed curves [42]. These curves were used to calculate the calibration intercept a (assessing whether the number of predicted events matches the number of observed events) and slope bL (assessing the tendency for extreme or uninformative predictions) [43]. The unreliability index was then calculated, which evaluates H0: a = 0 and bL = 1 using a single 2-df chi square test.
Variable importance
Variable importance was assessed by standardized logistic regression coefficients and ranger’s random forest permutation importance.
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Statistical software and reproducibility
R version 3.6.1 was used for all analyses. A comprehensive list of packages is provided in the Data Supplement. Annotated statistical code has been included in the Data Supplement and is available in native format on request.
This study was approved by the University of British Columbia Clinical Research Ethics Board, with waiver for informed consent. All methods were performed in concordance with institutional ethics guidelines and regulations.
Results
Cohort and chart review
Of 971 unique participants identified by procedure code, 729 were included in the analytic data set. This dataset was split by year into train (year 2008–2015, n = 614) and test sets (year 2016, n = 114). Participant characteristics are summarized in Table 2. Between-rater agreement was very strong for symptomatic status (Kappa = 0.846, n = 21).
Table 2
Characteristics of included participants by train and test population, Vancouver, Canada, 2008–2016. P-values reported for t-test (age) and Fisher exact test (all other variables)
Train
Test
P-value
N
615
114
Data years
2008–2015
2016
Age – mean (SD)
72.1 (9.1)
71.3 (9.7)
0.4
Female – N (%)
207 (33.7%)
33 (28.9%)
0.4
In metro – N (%)
482 (78.4%)
89 (78.1%)
1
Symptom type – N (%)
0.02
Asymptomatic
189 (30.7%)
29 (25.4%)
Retinal
111 (18.0%)
22 (19.3%)
TIA
198 (32.2%)
27 (23.7%)
Stroke
117 (19.0%)
36 (31.6%)
Sensitivity
Model sensitivity is summarized in Fig. 1A. Within the combined train and test sets, RuleDX was 32.8% (95% CI 29–37%) sensitive and 98.6% specific (96–100%). Within the train set, LogisticDX, LogisticAll and ForestALL were more sensitive than RuleDX at the 98.6% specificity margin. LogisticHOSP was less sensitive in the train set, so performance in the test set was not assessed. Test set confidence intervals for LogisticAll and ForestAll did not overlap with RuleDX, confirming the higher sensitivity of these models (95% CI 59–82% and 69–88%, respectively).
Fig. 1
Model performance assessed by sensitivity at 98.6% specificity (panel A) and area under the receiver operating characteristic curve (panel B). The diagnosis-only rule-based method involves no parameter tuning, so it is reported for all participants. All other models are analysed by train and test population. Training results are calculated using cross-fold hold-outs and are plotted with mean and 95% confidence interval for standard error. Testing results are calculated using n = 2000 bootstrapped samples and are plotted by empiric 95% confidence interval. Area under the curve is not calculable for the rule-based diagnosis-only method
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Roc
Model ROC AUC is summarized in Fig. 1B. Within the train set, mean AUC was highest for LogisticALL and ForestALL (0.938 ± 0.003 and 0.933 ± 0.003), intermediate for LogisticDX (0.918 ± 0.004) and lowest for LogisticHOSP (0.722 ± 0.006). Within the test set, AUC 95% CI for LogisticAll and ForestAll (0.893–0.977 and 0.906–0.979) excluded LogisticHOSP (0.726–0.879) and overlapped with LogisticDx (0.809–0.960). Test set ROC curves (Fig. 2A) highlight the discordance in AUC and sensitivity at the high specificity margin for LogisticHOSP and LogisticDX.
Fig. 2
Model performance in the test set by receiver operator characteristic curve (panel A), observed vs. predicted probability calibration curve (panel B). In panel A, a grey bar is positioned at specificity 98–100%, highlighting the limited sensitivity of LogisticDX at this margin
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Calibration
LOESS-smoothed calibration curves are provided in Fig. 2B and summary statistics for calibration are provided in Supplementary Table 4. All logistic regression models approximated the identity line, consistent with good calibration-in-the-large (intercept) and weak calibration (slope). The unreliability index for the ForestALL calibration curve was marginally significant (p-value 0.053), indicating probable deviation from the identity line.
Variable importance
Normalized logistic regression coefficients and random forest permutation importance metrics are presented in Fig. 3. Emergent hospital admission was weighted more heavily than discharge diagnoses. Physician diagnoses for stroke / TIA were heavily weighted, particularly those made by a neurologist. Fee items relating to the evaluation of probable ischemic symptoms, such as CT head, were moderately weighted.
Fig. 3
Standardized logistic regression model coefficients and random forest permutation importance for each model. Negative coefficients are shaded in light grey. Variables are sorted by importance in the first model in which they appear
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Discussion
In a cohort of participants with known CEA, rule-based classification by hospital discharge diagnosis was highly specific but insensitive for symptomatic status. The results of our study are concordant with a previous chart review [6] and likely explain implausibly low rates of symptomatic intervention observed in some administrative data studies [13, 18]. Given the available evidence, it is unlikely that this current state method will yield valid cohorts for population-level study of asymptomatic intervention.
We believe that the low sensitivity of diagnostic codes for symptomatic status is an expected side effect of Canadian discharge coding regulation. If a patient is initially admitted for a symptomatic event, such as an ischemic stroke, and undergoes unscheduled surgery on the same admission, the symptomatic event is correctly coded as either a most responsible diagnosis or preadmit comorbidity diagnosis type. These patients are likely to be correctly classified by a diagnosis-code only system. However, if the patient is admitted for scheduled surgery after their initial symptomatic event, then neither of these types can be used. It would be possible to code the ischemic event as a secondary diagnosis type, but this would also include ischemic events not relevant to the procedure. We do not see an obvious way to remedy this.
As an alternative to rule-based classification by discharge diagnosis, we explored the impact of increasingly complex ML models. To allow a direct comparison against rule-based classification, we evaluated all models by sensitivity at fixed high specificity. Our simplest model, elastic net with hospital discharge variables, performed no better by this metric in the training set and was not evaluated further. Adding physician claims diagnoses improved sensitivity in the training set but was inconsistently sensitive in the test set.
We hypothesized that two novel variable types might improve upon this result. First, we included a limited set of specialist-specific diagnoses, such as TIA diagnosed by neurologist, reasoning that these would be more predictive of true symptomatic status a diagnosis of TIA by a non-neurologist. Second, we identified a set of services, such as head CT, that might signal the investigation of a symptomatic event. Variables from both of these types were heavily weighted in both the logistic regression and random forest models, suggesting they are discriminating for symptomatic status. Performance of a head CT was especially important to the random forest model, reflecting its status as an essential investigation in the investigation of any central nervous system symptom. Incorporating these variables substantially improved model performance, in particular sensitivity at the high specificity margin. We believe that the gains in model performance justify the modest increase in data processing and model complexity.
We additionally evaluated whether a random forest model would be more discriminating than logistic regression. Although a marginal improvement in training set AUC was observed, confidence intervals for the test set essentially overlapped. We do not think that the small potential gain in discrimination justifies the increase in model complexity and loss of interpretability. It may be the case that the specific advantages of the forest were not relevant to this dataset. In addition, the strong performance of the logistic regression model yielded little grounds for improvement.
All logistic models appear well calibrated by plot and the unreliability index statistic. This suggests that our models were reasonably resilient against concept drift that might have occurred between the training and test data years (2008–2015 vs. 2016). Notably, the number of asymptomatic patients in our sample is small (n = 29), which limits the power of graphical methods and statistical tests to identify calibration errors [43].
While a strength of this study is its access to population-based physician claim and hospital discharge data, the use of single center to construct our cohort is a limitation. The resulting models likely include some practice-style features specific to this study’s jurisdiction. For example, the occasional use of the diagnostic code for demyelinating diseases is potentially specific to our jurisdiction and may not generalize. A second limitation of this study is the use of a test set drawn from the same institution. This limits the generalizability of the study to new populations and should be addressed by external validation using a nationally representative sample in future research. Finally, given restrictions on small cell size, we were not able to analyse classification accuracy for asymptomatic patients with peri-operative stroke. These patients are potentially at highest risk for misclassification by discharge diagnosis and are also the numerator cases for peri-operative complications. We thought it preferable to exclude these patients, rather than assume classification accuracy similar to the general population.
The intended future use case for this algorithm is to support national-scale quality monitoring programs for carotid endarterectomy. In this single-center study we demonstrate proof-of-concept for the use of administrative data for accurate classification of symptomatic status. Future work will need to evaluate the algorithm in nationally representative test and development sets. Ideally, the data set would be enriched with known cases of peri-operative complication, to ensure that the algorithm correctly classifies these high-importance cases.
Conclusion
Classification of symptomatic status for carotid endarterectomy by discharge diagnosis is insensitive. Logistic regression models combining physician claims and discharge data yield discriminating and well-calibrated models.
Acknowledgements
Arlo Adams – manuscript comments.
Population Data BC – data access. Note – all inferences, opinions, and conclusions drawn in this publication are those of the authors, and do not reflect the opinions or policies of the Data Steward(s).
Declarations
Ethics approval and consent to participate
This study was approved by the University of British Columbia Clinical Research Ethics Board, with waiver for informed consent. All methods were performed in concordance with institutional ethics guidelines and regulations.
Consent for publication
Not applicable.
Competing interests
None
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