Characterizing the Feasibility and Performance of Real-World Tumor Progression End Points and Their Association With Overall Survival in a Large Advanced Non-Small-Cell Lung Cancer Data Set.

PURPOSE: Large, generalizable real-world data can enhance traditional clinical trial results. The current study evaluates reliability, clinical relevance, and large-scale feasibility for a previously documented method with which to characterize cancer progression outcomes in advanced non-small-cell lung cancer from electronic health record (EHR) data. METHODS: Patients who were diagnosed with advanced non-small-cell lung cancer between January 1, 2011, and February 28, 2018, with two or more EHR-documented visits and one or more systemic therapy line initiated were identified in Flatiron Health's longitudinal EHR-derived database. After institutional review board approval, we retrospectively characterized real-world progression (rwP) dates, with a random duplicate sample to ascertain interabstractor agreement. We calculated real-world progression-free survival, real-world time to progression, real-world time to next treatment, and overall survival (OS) using the Kaplan-Meier method (index date was the date of first-line therapy initiation), and correlations between OS and other end points were assessed at the patient level (Spearman's ρ). RESULTS: Of 30,276 eligible patients,16,606 (55%) had one or more rwP event. Of these patients, 11,366 (68%) had subsequent death, treatment discontinuation, or new treatment initiation. Correlation of real-world progression-free survival with OS was moderate to high (Spearman's ρ, 0.76; 95% CI, 0.75 to 0.77; evaluable patients, n = 20,020), and for real-world time to progression correlation with OS was lower (Spearman's ρ, 0.69; 95% CI, 0.68 to 0.70; evaluable patients, n = 11,902). Interabstractor agreement on rwP occurrence was 0.94 (duplicate sample, n = 1,065) and on rwP date 0.85 (95% CI, 0.81 to 0.89; evaluable patients n = 358 [patients with two independent event captures within 30 days]). Median rwP abstraction time from individual EHRs was 18.0 minutes (interquartile range, 9.7 to 34.4 minutes). CONCLUSION: We demonstrated that rwP-based end points correlate with OS, and that rwP curation from a large, contemporary EHR data set can be reliable, clinically relevant, and feasible on a large scale.

Generating Real-World Tumor Burden Endpoints from Electronic Health Record Data: Comparison of RECIST, Radiology-Anchored, and Clinician-Anchored Approaches for Abstracting Real-World Progression in Non-Small Cell Lung Cancer.

INTRODUCTION: Real-world evidence derived from electronic health records (EHRs) is increasingly recognized as a supplement to evidence generated from traditional clinical trials. In oncology, tumor-based Response Evaluation Criteria in Solid Tumors (RECIST) endpoints are standard clinical trial metrics. The best approach for collecting similar endpoints from EHRs remains unknown. We evaluated the feasibility of a RECIST-based methodology to assess EHR-derived real-world progression (rwP) and explored non-RECIST-based approaches. METHODS: In this retrospective study, cohorts were randomly selected from Flatiron Health's database of de-identified patient-level EHR data in advanced non-small cell lung cancer. A RECIST-based approach tested for feasibility (N = 26). Three non-RECIST approaches were tested for feasibility, reliability, and validity (N = 200): (1) radiology-anchored, (2) clinician-anchored, and (3) combined. Qualitative and quantitative methods were used. RESULTS: A RECIST-based approach was not feasible: cancer progression could be ascertained for 23% (6/26 patients). Radiology- and clinician-anchored approaches identified at least one rwP event for 87% (173/200 patients). rwP dates matched 90% of the time. In 72% of patients (124/173), the first clinician-anchored rwP event was accompanied by a downstream event (e.g., treatment change); the association was slightly lower for the radiology-anchored approach (67%; 121/180). Median overall survival (OS) was 17 months [95% confidence interval (CI) 14, 19]. Median real-world progression-free survival (rwPFS) was 5.5 months (95% CI 4.6, 6.3) and 4.9 months (95% CI 4.2, 5.6) for clinician-anchored and radiology-anchored approaches, respectively. Correlations between rwPFS and OS were similar across approaches (Spearman's rho 0.65-0.66). Abstractors preferred the clinician-anchored approach as it provided more comprehensive context. CONCLUSIONS: RECIST cannot adequately assess cancer progression in EHR-derived data because of missing data and lack of clarity in radiology reports. We found a clinician-anchored approach supported by radiology report data to be the optimal, and most practical, method for characterizing tumor-based endpoints from EHR-sourced data. FUNDING: Flatiron Health Inc., which is an independent subsidiary of the Roche group.

Disparities in the Use of Programmed Death 1 Immune Checkpoint Inhibitors.

Amid growing excitement for immune checkpoint inhibitors of programmed death protein 1 (anti-PD1 agents), little is known about whether race- or sex-based disparities exist in their use. In this observational study, we constructed a large and mostly community-based cohort of patients with advanced stage cancers, including melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma, to compare the odds of receiving systemic treatment with or without anti-PD1 agents by race and by sex. In multivariable models that adjusted for age, stage, and number of prior anticancer therapies, we found no significant race-based disparities in anti-PD1 treatment. However, among patients with NSCLC, males had significantly higher odds of receiving anti-PD1 treatment compared with females (odds ratio 1.13, 95% confidence interval 1.02-1.24, p = .02). This finding suggests that as anti-PD1 agents enter the market to transform patient care, it will be critical to monitor for disparities in the use of these drugs.

Development and Validation of a High-Quality Composite Real-World Mortality Endpoint.

OBJECTIVE: To create a high-quality electronic health record (EHR)-derived mortality dataset for retrospective and prospective real-world evidence generation. DATA SOURCES/STUDY SETTING: Oncology EHR data, supplemented with external commercial and US Social Security Death Index data, benchmarked to the National Death Index (NDI). STUDY DESIGN: We developed a recent, linkable, high-quality mortality variable amalgamated from multiple data sources to supplement EHR data, benchmarked against the highest completeness U.S. mortality data, the NDI. Data quality of the mortality variable version 2.0 is reported here. PRINCIPAL FINDINGS: For advanced non-small-cell lung cancer, sensitivity of mortality information improved from 66 percent in EHR structured data to 91 percent in the composite dataset, with high date agreement compared to the NDI. For advanced melanoma, metastatic colorectal cancer, and metastatic breast cancer, sensitivity of the final variable was 85 to 88 percent. Kaplan-Meier survival analyses showed that improving mortality data completeness minimized overestimation of survival relative to NDI-based estimates. CONCLUSIONS: For EHR-derived data to yield reliable real-world evidence, it needs to be of known and sufficiently high quality. Considering the impact of mortality data completeness on survival endpoints, we highlight the importance of data quality assessment and advocate benchmarking to the NDI.

Identifying risk factors associated with smear positivity of pulmonary tuberculosis in Kazakhstan.

BACKGROUND: Sputum smear-positive tuberculosis (TB) patients have a high risk of transmission and are of great epidemiological and infection control significance. Little is known about the smear-positive populations in high TB burden regions, such as Kazakhstan. The objective of this study is to characterize the smear-positive population in Kazakhstan and identify associated modifiable risk factors. METHODS: Data on incident TB cases' (identified between April 2012 and March 2014) socio-demographic, risk behavior, and comorbidity characteristics were collected in four regions of Kazakhstan through structured survey and medical record review. We used multivariable logistic regression to determine factors associated with smear positivity. RESULTS: Of the total sample, 193 (34.3%) of the 562 study participants tested smear-positive. In the final adjusted multivariable logistic regression model, sex (adjusted odds ratio (aOR) = 2.0, 95% CI:1.3-3.1, p < 0.01), incarceration (aOR = 3.6, 95% CI:1.2-11.1, p = 0.03), alcohol dependence (aOR = 2.6, 95% CI:1.2-5.7, p = 0.02), diabetes (aOR = 5.0, 95% CI:2.4-10.7, p < 0.01), and physician access (aOR = 2.7, 95% CI:1.3-5.5p < 0.01) were associated with smear-positivity. CONCLUSIONS: Incarceration, alcohol dependence, diabetes, and physician access are associated with smear positivity among incident TB cases in Kazakhstan. To stem the TB epidemic, screening, treatment and prevention policies should address these factors.

Application of PCR-LDR-nucleic acid detection strip in detection of YMDD mutation in hepatitis B patients treated with lamivudine.

Chronic hepatitis B virus (CHBV) infection causes cirrhosis and hepatocellular carcinoma. Lamivudine (LAM) has been successfully used to treat CHBV infections but prolonged use leads to the emergence of drug-resistant variants. This is primarily linked to a mutation in the tyrosine-methionine-aspartate-aspartate (YMDD) motif of the HBV polymerase gene at position 204. Rapid diagnosis of drug-resistant HBV is necessary for a prompt treatment response. Common diagnostic methods such as sequencing and restriction fragment length polymorphism (RFLP) analysis lack sensitivity and require significant processing. The aim of this study was to demonstrate the usefulness of a novel diagnostic method that combines polymerase chain reaction (PCR), ligase detection reaction (LDR) and a nucleic acid detection strip (NADS) in detecting site-specific mutations related to HBV LAM resistance. We compared this method (PLNA) to direct sequencing and RFLP analysis in 50 clinical samples from HBV infected patients. There was 90% concordance between all three results. PLNA detected more samples containing mutant variants than both sequencing and RFLP analysis and was more sensitive in detecting mixed variant populations. Plasmid standards indicated that the sensitivity of PLNA is at or below 3,000 copies per ml and that it can detect a minor variant at 5% of the total viral population. This warrants its further development and suggests that the PLNA method could be a useful tool in detecting LAM resistance.