Construction of a composite surrogate marker of the long-term survival: application to kidney transplantation – CSM (Composite Surrogate Marker)

More than 250000 Europeans are living with a graft and 80000 people are enrolled in the waiting list. Given the limited availability of donor, it is of importance to improve graft survival. The goal of our proposal is to define an appropriate methodology to assess the prognostic capacity of a composite marker to evaluate long-term graft survival. Those tools will 1. Improve the allocation of the available graft to minimize the return to dialysis and the recipient mortality; 2. Help clinicians in the care of the patients (drugs, monitoring,…); 3. Constitute a new marker to monitor the graft survival to reduce the cost, the length and the risk of clinical studies.

New and innovative methodological strategies have to be design to shift from the monitoring of a single parameter (i-e graft and patient survival) to a composite marker that will fit better to the clinical reality. Preliminary studies have shown that multi-state based strategies are suitable to evaluate the clinical evolution of the patient, as such strategies take into account the evolution and distinguish two non-comparable failures (the return to dialysis and the death of the recipient). Our multi-state model will consider 4 different status: recipient without acute rejection, recipient with at least one episode of acute rejection, recipient that have return to dialysis and dead recipient with a functional graft. The primary objective is to define a composite variable that could predict the transition of the patient from one status to another. The transition from one status to another will be modelized using a semi-Markov based parametric strategy. Variables will be summarized by neuron networks, an optimal methodology to consider a great number of parameters in a flexible manner. Neuron networks have not been often used in medicine in contrast to other field, and thus strengthen the novelty of our proposal. Our multi-state model will be built based on the clinical record in order to predict the future evolution of the graft. Relative survival will be included to estimate the transition to the death with a functional graft (mortality in the general population).

All the socio-demographic and clinical variables will be obtained from the DIVAT database, database which was created in 1990. This database is the only one in Europe to have a dedicated quality policy. We aim to implement this quality policy by designing automatic audit tool of the data. We think that our multi-state model will benefit from the inclusion of emerging biomarkers (identified in the biocollection that is linked with DIVAT), even if such biomarkers have not been yet validated in large prospective cohort of patients.

To summarize, our project is defined by 3 specific aims: 1. To construct a complet database with clinical and biological parameters; 2. To design an innovative statistical strategy that will consider the heterogeneity of the recorded parameters to minimize the error in graft and patient evolution; 3. To built a new tool to assist physicians in their decision.

The expertise in designing a complex statistical methodology and the appraisal of multiple parameters (both clinical and socio-demographic) are the strength of our proposal.