Data-driven Derivation and Validation of Novel Phenotypes for Acute Kidney Transplant Rejection using Semi-supervised Clustering
Authors: Vaulet Thibaut , Divard Gillian , Thaunat Olivier , Lerut Evelyne , Senev Aleksandar , Aubert Olivier , Van Loon Elisabet , Callemeyn Jasper , Emonds Marie-Paule , Van Craenenbroeck Amaryllis , De Vusser Katrien , Sprangers Ben , Rabeyrin Maud , Dubois Valérie , Kuypers Dirk , De Vos Maarten , Loupy Alexandre , De Moor Bart , Naesens Maarten 
Published: March 2021

Significance Statement
The current Banff classification of kidney transplant rejection is on the basis of complex and discretionary combinations of histologic scores. As a purely empiric classification, it was not primarily developed to reflect clinically meaningful outcomes such as graft failure, and allows ambiguous phenotypes to overlap. This paper describes the use of data-driven clustering methods to produce a phenotypic reclassification of kidney transplant rejection that is both histologically and clinically relevant. Six novel cluster phenotypes are validated on external data. Each of these new phenotypes is significantly associated with graft failure and overcomes the current limitations of intermediate and mixed phenotypes. The data-driven phenotypic reclassification of kidney transplant rejection is a proof of concept, opening future research directions.

Background
Over the past decades, an international group of experts iteratively developed a consensus classification of kidney transplant rejection phenotypes, known as the Banff classification. Data-driven clustering of kidney transplant histologic data could simplify the complex and discretionary rules of the Banff classification, while improving the association with graft failure.

Methods
The data consisted of a training set of 3510 kidney-transplant biopsies from an observational cohort of 936 recipients. Independent validation of the results was performed on an external set of 3835 biopsies from 1989 patients. On the basis of acute histologic lesion scores and the presence of donor-specific HLA antibodies, stable clustering was achieved on the basis of a consensus of 400 different clustering partitions. Additional information on kidney-transplant failure was introduced with a weighted Euclidean distance.

Results
Based on the proportion of ambiguous clustering, six clinically meaningful cluster phenotypes were identified. There was significant overlap with the existing Banff classification (adjusted rand index, 0.48). However, the data-driven approach eliminated intermediate and mixed phenotypes and created acute rejection clusters that are each significantly associated with graft failure. Finally, a novel visualization tool presents disease phenotypes and severity in a continuous manner, as a complement to the discrete clusters.

Conclusions
A semisupervised clustering approach for the identification of clinically meaningful novel phenotypes of kidney transplant rejection has been developed and validated. The approach has the potential to offer a more quantitative evaluation of rejection subtypes and severity, especially in situations in which the current histologic categorization is ambiguous.