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Background & Aims: NIS4® is a blood-based non-invasive test designed to effectively rule in/rule out at-risk non-alcoholic steatohepatitis (NASH), defined as non-alcoholic fatty liver disease activity score ≥4 and significant fibrosis (stage ≥2), among patients with metabolic risk factors. Robustness of non-invasive test scores across characteristics of interest including age, type 2 diabetes mellitus, and sex, and optimised analytical aspects are critical for large-scale implementation in clinical practice. We developed and validated NIS2+™, an optimisation of NIS4®, specifically designed to improve score robustness., Methods: A well-balanced training cohort (n = 198) included patients from the GOLDEN-505 trial. The validation (n = 684) and test (n = 2,035) cohorts included patients from the RESOLVE-IT trial. Well-matched subgroups were created to avoid potential confounding effects during modelling and analysis of score robustness. Models were trained using logistic regressions for at-risk NASH detection and compared using Bayesian information criteria. Performance of NIS2+™ was compared with that of NIS4®, Fibrosis-4, and alanine aminotransferase using area under the receiver operating characteristic curve, and robustness was analysed through score distribution., Results: Using the training cohort to compare all combinations of NIS4® biomarkers, NIS2 (miR-34a-5p, YKL-40) was identified as the best combination of parameters. To correct for the sex effect on miR-34a-5p (validation cohort), sex and sex ∗ miR-34a-5p parameters were added, creating NIS2+™. In the test cohort, NIS2+™ exhibited a statistically higher area under the receiver operating characteristic curve (0.813) vs. NIS4® (0.792; p = 0.0002), Fibrosis-4 (0.653; p <0.0001), and alanine aminotransferase (0.699; p <0.0001). NIS2+™ scores were not affected by age, sex, BMI, or type 2 diabetes mellitus status, providing robust clinical performances irrespective of patient characteristics., Conclusion: NIS2+™ constitutes a robust optimisation of NIS4® technology for the detection of at-risk NASH., Impact and Implications: The development of non-invasive tests for accurate, large-scale detection of patients with at-risk non-alcoholic steatohepatitis (NASH; defined as NASH with non-alcoholic fatty liver disease activity score ≥4 and fibrosis stage ≥2) - who are at higher risk for disease progression and for developing liver-related life-threatening outcomes - is critical for identifying this patient population in the clinical setting and improving the screening process of NASH clinical trials. We report the development and validation of NIS2+™, a diagnostic test designed as an optimisation of NIS4® technology, a blood-based panel currently used to detect at-risk NASH in patients with metabolic risk factors. NIS2+™ showed improved performance for the detection of at-risk NASH compared with NIS4® and other non-invasive liver tests that was not impacted by patients' characteristics of interest, such as age, sex, type 2 diabetes mellitus, BMI, dyslipidaemia, and hypertension. This makes NIS2+™ a robust and reliable tool for the diagnosis of at-risk NASH among patients with metabolic risk factors, and an effective candidate for large-scale implementation in clinical practice and clinical trials., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)