Penalized regression for left-truncated and right-censored survival data

McGough, Sarah F.; Incerti, Devin; Lyalina, Svetlana; Copping, Ryan; Narasimhan, Balasubramanian; Tibshirani, Robert

doi:10.1101/2021.02.09.21251373

Cited by 4 publications

(5 citation statements)

References 33 publications

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“…Overall survival (OS) was calculated from start of treatment to death from any cause, and patients with no record of mortality were right censored at the date of last clinic visit or structured activity. Because patients cannot enter the database until a CGP report is delivered, OS risk intervals were left truncated to the date of CGP report to account for immortal time (23,24). Flatiron Health database mortality information is a composite derived from 3 sources: documents within the EHR, Social Security Death Index, and a commercial death dataset mining data from obituaries and funeral homes.…”

Section: Discussionmentioning

confidence: 99%

Real-world Validation of TMB and Microsatellite Instability as Predictive Biomarkers of Immune Checkpoint Inhibitor Effectiveness in Advanced Gastroesophageal Cancer

Graf

Fisher

Creeden

et al. 2022

Cancer Research Communications

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Patients with advanced gastroesophageal cancer (mEG) and tumor mutational burden ≥ 10 mut/mb (TMB≥10) have more favorable outcomes on immune checkpoint inhibitor (ICPI) monotherapy compared to chemotherapy in subgroup analyses of randomized controlled trials. We sought to evaluate the robustness of these associations in real-world settings where patients and practices are more diverse. 362 2L and 692 1L patients respectively received ICPI (n = 99, 33) or chemotherapy (n = 263, 659) across approximately 280 U.S. academic or community-based cancer clinics March 2014-July 2021. De-identified data was captured into a real-world clinico-genomic database (CGDB). All patients underwent Foundation Medicine testing. Time to next treatment (TTNT) and overall survival (OS) comparing ICPI vs. chemotherapy were adjusted for treatment assignment imbalances using propensity scores. 2L: TMB≥10 had more favorable TTNT (Median 24 vs. 4.1 months, HR: 0.19, 95%CI: 0.09–0.44, p=0.0001) and OS (median 43.1 vs. 6.2 months, HR: 0.24, 95%CI: 0.011–0.54, p=0.0005), TMB<10 did not (p>0.05). 1L: TMB≥10 had more favorable TTNT (not reached vs. median 4.1 months, HR: 0.13, 95%CI: 0.03–0.48, p=0.0024) and OS (not reached vs. median 17.1 months, HR: 0.30, 95%CI: 0.08–1.14, p=0.078), TMB<10 had less favorable TTNT (median 2.8 vs. 6.5 months, HR: 2.36, 95%CI: 1.25–4.45, p=0.008) and OS (median 4.5 vs. 13.1 months, HR: 1.82, 95%CI: 0.87–3.81, p=0.11). TMB ≥ 10 robustly identifies mEG patients with more favorable outcomes on 2L ICPI monotherapy vs. chemotherapy. 1L data are more limited, but effects are consistent with 2L.

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Section: Discussionmentioning

confidence: 99%

Real-world Validation of TMB and Microsatellite Instability as Predictive Biomarkers of Immune Checkpoint Inhibitor Effectiveness in Advanced Gastroesophageal Cancer

Graf

Fisher

Creeden

et al. 2022

Cancer Research Communications

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“…In survival analysis, left truncation bias 28 was corrected by considering only the time between patient sampling and time of death. Left truncation bias occurs when risk of death is measured over a time in which it could not have occurred; by definition a patient who had already died could not have been recruited into a study.…”

Section: Discussionmentioning

confidence: 99%

“…The rationale is to exclude survival time that occurred before sampling, because the patient could not, by definition, have died during this period. Analysis of left truncated data can lead to false positive associations 28 , however, left truncation bias correction can lead to under-powered analysis because of the loss of information. As a result, we report both results for analysis in both the Project MinE and AnswerALS cohorts.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial function determines severity but not risk of amyotrophic lateral sclerosis

Harvey

Weinreich

Zhang

et al. 2022

Preprint

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Selective vulnerability of energy-intensive motor neurons (MNs) has fostered speculation that mitochondrial function is a determinant of ALS. Previously, the position of mitochondrial function in the pathogenic cascade leading to neurotoxicity has been unclear. We separated upstream genetic determinants of mitochondrial function, including genetic variation within the mitochondrial genome or autosomes; from downstream changeable factors including mitochondrial copy number (mtCN) and MN gene expression. We discovered that functionally validated mitochondrial haplotypes are a determinant of ALS survival but not ALS risk. Loss-of-function genetic variants within, and reduced MN expression of, ACADM and DNA2 lead to shorter ALS survival; both genes impact mitochondrial function. MtCN responds dynamically to the onset of ALS independent of mitochondrial haplotype, and is also significantly correlated with disease severity. We conclude that mitochondrial function impacts ALS progression but not risk; our findings have therapeutic implications.

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“…Here we use the same set of confounders as 𝑋 in the odds ratio analysis. To avoid the immortal time bias that may arise from death before getting the chance to take genomic profiling tests 44 , we penalized the Cox proportional hazards model with left-truncation method with the dates when patients receive the FMI tests 47 .…”

Section: Odds Ratio Evaluating Associations Between Patient Character...mentioning

confidence: 99%

Systematic analysis of off-label and off-guideline cancer therapy usage in a real-world cohort of 153,122 U.S. patients

Liu

Wang²,

Rizzo³

et al. 2023

Preprint

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Patients with cancer may be given treatments that are not officially approved (off-label) or recommended by guidelines (off-guideline) for multiple reasons including a lack of effective approved treatments. Here we present a systematic characterization of the patterns of off-label and off-guideline usage in 153,122 U.S. patients with 14 common cancer types using a large electronic health record (EHR)-derived de-identified database. We find that 18.3% and 3.9% of patients have received at least one line of off-label and off-guideline cancer drugs, respectively. Out of the 14 malignancies investigated, advanced bladder cancer has the highest proportion with 8.1% of patients receiving off-guideline treatments, most of which are recommended for non-small cell lung cancer. Patients with worse performance status, in later lines, or treated at academic hospitals are significantly more likely to receive off-label and off-guideline drugs. Underrepresented minority patients are less likely to receive off-guideline treatments in several cancer types. To quantify how predictable off-guideline usage is, we developed machine learning models to predict which drug a patient is likely to receive based on their clinical characteristics and previous treatments. Finally, we demonstrate that our systematic analysis of large real-world cohorts can identify interesting candidates for potential label expansion by identifying off-label treatments that demonstrate effectiveness in the real world setting. For example, we find that hormonal agents approved for breast cancer are used off-label in patients with ovarian cancer. Moreover, these hormonal agents show promising effectiveness in ovarian cancer with adjusted hazard ratio 0.53 (0.44, 0.65) compared to standard-of-care. This work demonstrates the power of large-scale computational analysis of real-world data for investigating non-standard cancer treatment usages.

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Penalized regression for left-truncated and right-censored survival data

Cited by 4 publications

References 33 publications

Real-world Validation of TMB and Microsatellite Instability as Predictive Biomarkers of Immune Checkpoint Inhibitor Effectiveness in Advanced Gastroesophageal Cancer

Real-world Validation of TMB and Microsatellite Instability as Predictive Biomarkers of Immune Checkpoint Inhibitor Effectiveness in Advanced Gastroesophageal Cancer

Mitochondrial function determines severity but not risk of amyotrophic lateral sclerosis

Systematic analysis of off-label and off-guideline cancer therapy usage in a real-world cohort of 153,122 U.S. patients

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