An Automated Gene Expression-Based Platform for Multidimensional Assessment and Interpretation of Kidney Allograft Biopsies: Development and Multicenter External Validation (HistoMX)
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 发起方
- 入组人数
- 2,410
- 主要终点
- Discrimination of molecular diagnostic classifiers (AUROC)
研究概览
简要总结
This retrospective multicentre observational study developed and validated HistoMX, an automated gene-expression-based platform for multidimensional molecular interpretation of kidney allograft biopsies.
The study included 2,410 archived post-transplant kidney allograft biopsy samples from adult kidney transplant recipients. Formalin-fixed paraffin-embedded biopsy tissue was profiled using the Banff Human Organ Transplant panel on the NanoString nCounter platform. HistoMX integrates locked preprocessing, quality control, single-sample normalization, diagnostic classification, Banff lesion-level modelling, molecular lesion-severity scores, composite injury indices, immune-cell estimation, pathway-enrichment analysis, and automated clinician-facing reporting.
The platform was evaluated against reference histology based on the Banff classification. HistoMX was designed to complement, not replace, conventional histopathology by providing standardized molecular evidence across diagnostic, lesion-level, continuous injury, and biological dimensions of kidney allograft injury.
详细描述
Kidney allograft biopsy interpretation remains central to post-transplant care, but conventional histology may not fully capture the biological continuum of alloimmune and non-alloimmune injury. Targeted transcriptomic profiling of formalin-fixed paraffin-embedded biopsy tissue using the Banff Human Organ Transplant panel provides a practical molecular layer aligned with routine pathology workflows.
HistoMX was developed as an automated molecular interpretation platform intended to transform B-HOT nCounter expression data into standardized diagnostic probabilities, molecular lesion scores, composite injury indices, immune-cell estimates, pathway-enrichment outputs, and a clinician-facing report.
HistoMX was developed and validated using 2,410 post-transplant kidney allograft biopsies from adult recipients across eleven transplant centers in Europe and North America. The population comprised a development cohort (including 7 centers: PITOR [Saint-Louis, Necker], Montpellier, Lille, Bordeaux, Toulouse, Barcelona, and Cedars-Sinai Medical Center) and three independent external validation cohorts (Arkana Laboratories, USA, Massachusetts General Hospital, USA, and University of Alberta, Canada).
The development cohort included 693 adult kidney transplant recipients contributing to 764 biopsies collected between 2004 and 2021 across eight centres in Europe and North America. This cohort was split, stratified by main histological diagnosis, into a derivation set of 571 biopsies and an internal validation set of 193 biopsies. The derivation set was used for feature selection, model development, hyperparameter tuning, and estimation of preprocessing and normalization parameters. The internal validation set was kept independent from all model-development steps.
External validation was performed in three independent cohorts: Arkana Laboratories, USA, with 1,309 biopsies; Massachusetts General Hospital, USA, with 241 biopsies; and the University of Alberta / Alberta University Hospital, Canada, with 96 biopsies. The same eligibility and assay-quality criteria were applied to the external validation cohorts.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Retrospective
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Adult kidney transplant recipient, defined as age 18 years or older at transplantation
- •Post-transplant kidney allograft biopsy
- •Archived FFPE kidney allograft biopsy tissue is available and suitable for transcriptomic profiling
- •Biopsy submitted for B-HOT nCounter transcriptomic profiling
- •Available Banff reference pathology diagnosis
- •Available Banff lesion information required for endpoint definition
- •Sample meeting prespecified nCounter assay quality-control criteria
排除标准
- •Recipient age <18 years at transplantation
- •Multi-organ transplantation
- •Pre-transplant biopsy
- •Missing Banff reference pathology diagnosis
- •Failure of prespecified nCounter quality-control criteria
- •Missing or insufficient data required to define the relevant reference endpoint
研究组 & 干预措施
Massachussets General Hospital cohort
Monocenter External validation cohort. Retrospective. No intervention.
Arkana Laboratories cohort
External validation cohort. Retrospective available on NCBI. No extervention.
Development cohort
Multicenter Development cohort. Retrospective. No intervention.
Alberta cohort
Monocenter External validation cohort. Retrospective. No intervention.
结局指标
主要结局
Discrimination of molecular diagnostic classifiers (AUROC)
时间窗: At baseline defined by kidney allograft biopsy (single time-point assessment).
Area under the ROC curve for prediction of each main diagnostic category (antibody-mediated rejection, T cell-mediated rejection, any rejection, BK virus nephropathy, acute tubular injury without rejection, no-active-inflammatory complication) versus the Banff reference histological diagnosis, in internal and external validation cohorts.
Calibration of molecular diagnostic classifiers (Brier score, log loss)
时间窗: At baseline defined by kidney allograft biopsy (single time-point assessment).
Calibration of predicted diagnostic probabilities for each main diagnostic endpoint, assessed using calibration plots, calibration intercept and slope, Brier score, and log loss, compared with the Banff reference histological diagnosis.
次要结局
- Precision-recall performance (AUPRC) of molecular diagnostic classifiers(At baseline defined by kidney allograft biopsy (single time-point assessment).)
- Discrimination of Banff lesion classifiers (AUROC) for binary lesion.(At baseline defined by kidney allograft biopsy (single time-point assessment).)
- Correlation of continuous molecular lesion-severity scores with histological Banff grades.(At baseline defined by kidney allograft biopsy (single time-point assessment).)
- Performance of composite molecular injury indices (AMR/MVI, TCMR/TI, activity, chronicity).(At baseline defined by kidney allograft biopsy (single time-point assessment).)
- Validation of cell-deconvolution estimates(At baseline defined by kidney allograft biopsy (single time-point assessment).)
- Concordance between molecular and histological diagnoses(At baseline defined by kidney allograft biopsy (single time-point assessment).)