Robust-ComBat: Mitigating Outlier Effects in Diffusion MRI Data Harmonization

Harmonization methods such as ComBat and its variants are widely used to mitigate diffusion MRI (dMRI) site-specific biases. However, ComBat assumes that subject distributions exhibit a Gaussian profile. In practice, patients with neurological disorders often present diffusion metrics that deviate markedly from those of healthy controls, introducing pathological outliers that distort site-effect estimation. This problem is particularly challenging in clinical practice as most patients undergoing brain imaging have an underlying and yet undiagnosed condition, making it difficult to exclude them from harmonization cohorts, as their scans were precisely prescribed to establish a diagnosis. In this paper, we show that harmonizing data to a normative reference population with ComBat while including pathological cases induces significant distortions. Across 7 neurological conditions, we evaluated 10 outlier rejection methods with 4 ComBat variants over a wide range of scenarios, revealing that many filtering strategies fail in the presence of pathology. In contrast, a simple MLP provides robust outlier compensation enabling reliable harmonization while preserving disease-related signal. Experiments on both control and real multi-site cohorts, comprising up to 80% of subjects with neurological disorders, demonstrate that Robust-ComBat consistently outperforms conventional statistical baselines with lower harmonization error across all ComBat variants.

Clinical-ComBAT: a diffusion-weighted MRI harmonization method for clinical applications

Diffusion-weighted magnetic resonance imaging (DW-MRI) derived scalar maps are effective for assessing neurodegenerative diseases and microstructural properties of white matter in large number of brain conditions. However, DW-MRI inherently limits the combination of data from multiple acquisition sites without harmonization to mitigate scanner-specific biases. While the widely used ComBAT method reduces site effects in research, its reliance on linear covariate relationships, homogeneous populations, fixed site numbers, and well populated sites constrains its clinical use. To overcome these limitations, we propose Clinical-ComBAT, a method designed for real-world clinical scenarios. Clinical-ComBAT harmonizes each site independently, enabling flexibility as new data and clinics are introduced. It incorporates a non-linear polynomial data model, site-specific harmonization referenced to a normative site, and variance priors adaptable to small cohorts. It further includes hyperparameter tuning and a goodness-of-fit metric for harmonization assessment. We demonstrate its effectiveness on simulated and real data, showing improved alignment of diffusion metrics and enhanced applicability for normative modeling.

ComBAT Harmonization for diffusion MRI: Challenges and Best Practices

Over the years, ComBAT has become the standard method for harmonizing MRI-derived measurements, with its ability to compensate for site-related additive and multiplicative biases while preserving biological variability. However, ComBAT relies on a set of assumptions that, when violated, can result in flawed harmonization. In this paper, we thoroughly review ComBAT's mathematical foundation, outlining these assumptions, and exploring their implications for the demographic composition necessary for optimal results. Through a series of experiments involving a slightly modified version of ComBAT called Pairwise-ComBAT tailored for normative modeling applications, we assess the impact of various population characteristics, including population size, age distribution, the absence of certain covariates, and the magnitude of additive and multiplicative factors. Based on these experiments, we present five essential recommendations that should be carefully considered to enhance consistency and supporting reproducibility, two essential factors for open science, collaborative research, and real-life clinical deployment.