Andrew P. Stubbs | TU Delft Repository

Tacrolimus Exposure is Associated with Acute Rejection in the Early Phase After Kidney Transplantation

A Joint Modeling Approach

Journal article (2025) - Maaike R. Schagen, Alvaro Assis de Souza, Karin Boer, Jesse H. Krijthe, Rachida Bouamar, Andrew P. Stubbs, Dennis A. Hesselink, Brenda C.M. de Winter

Background: – Reports regarding the relationship between tacrolimus exposure and the risk of acute kidney allograft rejection are conflicting. This may be explained by the previous use of methodological approaches that disregarded important factors in the analysis of longitudinal measurements and time-to-event data. Therefore, in this study, joint models were used to investigate the relationship between repeated measurements of tacrolimus predose concentrations (C ₀) and time to acute biopsy-proven acute rejection (BPAR).Methods: – This was a post hoc analysis of a randomized controlled trial in which living-donor kidney transplant recipients (KTR) received either a standard, bodyweight-based or CYP3A5 genotype-based tacrolimus starting dose. Joint modeling was performed by coupling a mixed-effects model for tacrolimus C ₀ with a Cox proportional hazards model for the risk of rejection. Only the first episode of rejection was considered.Results: – A total of 229 KTRs were included, of whom the incidence of BPAR was 10.5% (n = 24 KTRs) in the first 3 months posttransplant. A total of 3069 tacrolimus measurements were available for the analysis. A joint model adjusted for recipient age and peak panel reactive antibodies demonstrated that tacrolimus C ₀ was associated with risk of rejection. A 1-unit increase in the time-normalized area under the curve for logarithmically (log)-transformed C ₀ represented a change of −2.65 in the log of the relative hazard (95% credible interval: −5.05 to −0.36, P = 0.022).Conclusions: – A negative association between the cumulative effect of tacrolimus C ₀ and BPAR was observed using joint modeling. This demonstrated that KTRs with lower tacrolimus exposure were at a higher risk of rejection. ...

Two-Step Transfer Learning Improves Deep Learning–Based Drug Response Prediction in Small Datasets

A Case Study of Glioblastoma

Journal article (2025) - Jie Ju, Ioannis Ntafoulis, Michelle Klein, Marcel J.T. Reinders, Martine Lamfers, Andrew P. Stubbs, Yunlei Li

While deep learning (DL) is used in patients’ outcome predictions, the insufficiency of patient samples limits the accuracy. In this study, we investigated how transfer learning (TL) alleviates the small sample size problem. A 2-step TL framework was constructed for a difficult task: predicting the response of the drug temozolomide (TMZ) in glioblastoma (GBM) cell cultures. The GBM is aggressive, and most patients do not benefit from the only approved chemotherapeutic agent TMZ. O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status is the only biomarker for TMZ responsiveness but has shown limited predictive power. The 2-step TL framework was built on 3 datasets: (1) the subset of the Genomics of Drug Sensitivity in Cancer (GDSC) dataset, including miscellaneous cell cultures treated by TMZ, cyclophosphamide, bortezomib, and oxaliplatin, as the source dataset; (2) the Human Glioblastoma Cell Culture (HGCC) dataset, for fine-tuning; and (3) a small target dataset GSE232173, for validation. The latter two included specifically TMZ-treated GBM cell cultures. The DL models were pretrained on the cell cultures treated by each of the 4 drugs from GDSC, respectively. Then, the DL models were refined on HGCC, where the best source drug was identified. Finally, the DL model was validated on GSE232173. Using 2-step TL with pretraining on oxaliplatin was not only superior to those without TL and with 1-step TL but also better than 3 benchmark methods, including MGMT. The oxaliplatin-based TL improved the performance probably by increasing the weights of cell cycle-related genes, which relates to the TMZ response processes. Our findings support the potential of oxaliplatin being an alternative therapy for patients with GBM and TL facilitating drug repurposing research. We recommend that following our methodology, using mixed cancers and a related drug as the source and then fine-tuning the model with the target cancer and the target drug will enhance drug response prediction. ...

While deep learning (DL) is used in patients’ outcome predictions, the insufficiency of patient samples limits the accuracy. In this study, we investigated how transfer learning (TL) alleviates the small sample size problem. A 2-step TL framework was constructed for a difficult task: predicting the response of the drug temozolomide (TMZ) in glioblastoma (GBM) cell cultures. The GBM is aggressive, and most patients do not benefit from the only approved chemotherapeutic agent TMZ. O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status is the only biomarker for TMZ responsiveness but has shown limited predictive power. The 2-step TL framework was built on 3 datasets: (1) the subset of the Genomics of Drug Sensitivity in Cancer (GDSC) dataset, including miscellaneous cell cultures treated by TMZ, cyclophosphamide, bortezomib, and oxaliplatin, as the source dataset; (2) the Human Glioblastoma Cell Culture (HGCC) dataset, for fine-tuning; and (3) a small target dataset GSE232173, for validation. The latter two included specifically TMZ-treated GBM cell cultures. The DL models were pretrained on the cell cultures treated by each of the 4 drugs from GDSC, respectively. Then, the DL models were refined on HGCC, where the best source drug was identified. Finally, the DL model was validated on GSE232173. Using 2-step TL with pretraining on oxaliplatin was not only superior to those without TL and with 1-step TL but also better than 3 benchmark methods, including MGMT. The oxaliplatin-based TL improved the performance probably by increasing the weights of cell cycle-related genes, which relates to the TMZ response processes. Our findings support the potential of oxaliplatin being an alternative therapy for patients with GBM and TL facilitating drug repurposing research. We recommend that following our methodology, using mixed cancers and a related drug as the source and then fine-tuning the model with the target cancer and the target drug will enhance drug response prediction.

Consensus molecular subtype classification of colorectal adenomas

Journal article (2018) - Malgorzata A. Komor, Linda J.W. Bosch, More Authors..., Gergana Bounova, Anne S. Bolijn, Pien M. Delis‐van Diemen, Christian Rausch, Youri Hoogstrate, Andrew P. Stubbs, Mark de Jong, Lodewyk F.A. Wessels

Consensus molecular subtyping is an RNA expression-based classification system for colorectal cancer (CRC). Genomic alterations accumulate during CRC pathogenesis, including the premalignant adenoma stage, leading to changes in RNA expression. Only a minority of adenomas progress to malignancies, a transition that is associated with specific DNA copy number aberrations or microsatellite instability (MSI). We aimed to investigate whether colorectal adenomas can already be stratified into consensus molecular subtype (CMS) classes, and whether specific CMS classes are related to the presence of specific DNA copy number aberrations associated with progression to malignancy. RNA sequencing was performed on 62 adenomas and 59 CRCs. MSI status was determined with polymerase chain reaction-based methodology. DNA copy number was assessed by low-coverage DNA sequencing (n = 30) or array-comparative genomic hybridisation (n = 32). Adenomas were classified into CMS classes together with CRCs from the study cohort and from The Cancer Genome Atlas (n = 556), by use of the established CMS classifier. As a result, 54 of 62 (87%) adenomas were classified according to the CMS. The CMS3 ‘metabolic subtype’, which was least common among CRCs, was most prevalent among adenomas (n = 45; 73%). One of the two adenomas showing MSI was classified as CMS1 (2%), the ‘MSI immune’ subtype. Eight adenomas (13%) were classified as the ‘canonical’ CMS2. No adenomas were classified as the ‘mesenchymal’ CMS4, consistent with the fact that adenomas lack invasion-associated stroma. The distribution of the CMS classes among adenomas was confirmed in an independent series. CMS3 was enriched with adenomas at low risk of progressing to CRC, whereas relatively more high-risk adenomas were observed in CMS2. We conclude that adenomas can be stratified into the CMS classes. Considering that CMS1 and CMS2 expression signatures may mark adenomas at increased risk of progression, the distribution of the CMS classes among adenomas is consistent with the proportion of adenomas expected to progress to CRC. ...

Consensus molecular subtyping is an RNA expression-based classification system for colorectal cancer (CRC). Genomic alterations accumulate during CRC pathogenesis, including the premalignant adenoma stage, leading to changes in RNA expression. Only a minority of adenomas progress to malignancies, a transition that is associated with specific DNA copy number aberrations or microsatellite instability (MSI). We aimed to investigate whether colorectal adenomas can already be stratified into consensus molecular subtype (CMS) classes, and whether specific CMS classes are related to the presence of specific DNA copy number aberrations associated with progression to malignancy. RNA sequencing was performed on 62 adenomas and 59 CRCs. MSI status was determined with polymerase chain reaction-based methodology. DNA copy number was assessed by low-coverage DNA sequencing (n = 30) or array-comparative genomic hybridisation (n = 32). Adenomas were classified into CMS classes together with CRCs from the study cohort and from The Cancer Genome Atlas (n = 556), by use of the established CMS classifier. As a result, 54 of 62 (87%) adenomas were classified according to the CMS. The CMS3 ‘metabolic subtype’, which was least common among CRCs, was most prevalent among adenomas (n = 45; 73%). One of the two adenomas showing MSI was classified as CMS1 (2%), the ‘MSI immune’ subtype. Eight adenomas (13%) were classified as the ‘canonical’ CMS2. No adenomas were classified as the ‘mesenchymal’ CMS4, consistent with the fact that adenomas lack invasion-associated stroma. The distribution of the CMS classes among adenomas was confirmed in an independent series. CMS3 was enriched with adenomas at low risk of progressing to CRC, whereas relatively more high-risk adenomas were observed in CMS2. We conclude that adenomas can be stratified into the CMS classes. Considering that CMS1 and CMS2 expression signatures may mark adenomas at increased risk of progression, the distribution of the CMS classes among adenomas is consistent with the proportion of adenomas expected to progress to CRC.