Investigator

Hein Putter

Professor · Leiden University Medical Center, Dept of Biomedical Data Sciences

HPHein Putter
Papers(2)
Analyzing Coarsened a…Molecular Classificat…
Collaborators(8)
Nanda HorewegJan Willem MensLars L. J. van der Bu…Ludy LutgensMarie A.D. HaverkortTjalling BosseJan JobsenCarien Creutzberg
Institutions(6)
Leiden UniversityErasmus McMaastro ClinicRadiotherapiegroepLeiden University Med…Medisch Spectrum Twen…

Papers

Analyzing Coarsened and Missing Data by Imputation Methods

ABSTRACTIn various missing data problems, values are not entirely missing, but are coarsened. For coarsened observations, instead of observing the true value, a subset of values ‐ strictly smaller than the full sample space of the variable ‐ is observed to which the true value belongs. In our motivating example for patients with endometrial carcinoma, the degree of lymphovascular space invasion (LVSI) can be either absent, focally present, or substantially present. For a subset of individuals, however, LVSI is reported as being present, which includes both non‐absent options. In the analysis of such a dataset, difficulties arise when coarsened observations are to be used in an imputation procedure. To our knowledge, no clear‐cut method has been described in the literature on how to handle an observed subset of values, and treating them as entirely missing could lead to biased estimates. Therefore, in this paper, we evaluated the best strategy to deal with coarsened and missing data in multiple imputation. We tested a number of plausible ad hoc approaches, possibly already in use by statisticians. Additionally, we propose a principled approach to this problem, consisting of an adaptation of the SMC‐FCS algorithm (SMC‐FCS: Coarsening compatible), that ensures that imputed values adhere to the coarsening information. These methods were compared in a simulation study. This comparison shows that methods that prevent imputations of incompatible values, like the SMC‐FCS method, perform consistently better in terms of a lower bias and RMSE, and achieve better coverage than methods that ignore coarsening or handle it in a more naïve way. The analysis of the motivating example shows that the way the coarsening information is handled can matter substantially, leading to different conclusions across methods. Overall, our proposed SMC‐FCS method outperforms other methods in handling coarsened data, requires limited additional computation cost and is easily extendable to other scenarios.

Molecular Classification Predicts Response to Radiotherapy in the Randomized PORTEC-1 and PORTEC-2 Trials for Early-Stage Endometrioid Endometrial Cancer

PURPOSE The molecular classification of endometrial cancer (EC) has proven to have prognostic value and is predictive of response to adjuvant chemotherapy. Here, we investigate its predictive value for response to external beam radiotherapy (EBRT) and vaginal brachytherapy (VBT) in early-stage endometrioid EC (EEC). METHODS Data of the randomized PORTEC-1 trial (n = 714) comparing pelvic EBRT with no adjuvant therapy in early-stage intermediate-risk EC and the PORTEC-2 trial (n = 427) comparing VBT with EBRT in early-stage high-intermediate-risk EC were used. Locoregional (including vaginal and pelvic) recurrence-free survival was compared between treatment groups across the four molecular classes using Kaplan-Meier's methodology and log-rank tests. RESULTS A total of 880 molecularly classified ECs, 484 from PORTEC-1 and 396 from PORTEC-2, were included. The majority were FIGO-2009 stage I EEC (97.2%). The median follow-up was 11.3 years. No locoregional recurrences were observed in EC with a pathogenic mutation of DNA polymerase-ε ( POLEmut EC). In mismatch repair–deficient (MMRd) EC, locoregional recurrence-free survival was similar after EBRT (94.2%), VBT (94.2%), and no adjuvant therapy (90.3%; P = .74). In EC with a p53 abnormality (p53abn EC), EBRT (96.9%) had a substantial benefit over VBT (64.3%) and no adjuvant therapy (72.2%; P = .048). In EC with no specific molecular profile (NSMP EC), both EBRT (98.3%) and VBT (96.2%) yielded better locoregional control than no adjuvant therapy (87.7%; P < .0001). CONCLUSION The molecular classification of EC predicts response to radiotherapy in stage I EEC and may guide adjuvant treatment decisions. Omitting radiotherapy seems to be safe in POLEmut EC. The benefit of radiotherapy seems to be limited in MMRd EC. EBRT yields a significantly better locoregional recurrence-free survival than VBT or no adjuvant therapy in p53abn EC. VBT is the treatment of choice for NSMP EC as it is as effective as EBRT and significantly better than no adjuvant therapy for locoregional tumor control.

602Works
2Papers
8Collaborators
1Trials

Positions

Professor

Leiden University Medical Center · Dept of Biomedical Data Sciences

Links & IDs
0000-0001-5395-1422

Researcher Id: C-2244-2018