Age

We establish a formal connection between the decades-old surrogate outcome model in biostatistics and economics and the emerging field of prediction-powered inference (PPI). The connection treats predictions from pre-trained models, prevalent in the age of AI, as cost-effective surrogates for expensive outcomes. Building on the surrogate outcomes literature, we develop recalibrated prediction-powered inference, a more efficient approach to statistical inference than existing PPI proposals. Our method departs from the existing proposals by using flexible machine learning techniques to learn the optimal ``imputed loss'' through a step we call recalibration. Importantly, the method always improves upon the estimator that relies solely on the data with available true outcomes, even when the optimal imputed loss is estimated imperfectly, and it achieves the smallest asymptotic variance among PPI estimators if the estimate is consistent. Computationally, our optimization objective is convex whenever the loss function that defines the target parameter is convex. We further analyze the benefits of recalibration, both theoretically and numerically, in several common scenarios where machine learning predictions systematically deviate from the outcome of interest. We demonstrate significant gains in effective sample size over existing PPI proposals via three applications leveraging state-of-the-art machine learning/AI models.

BrainAGE is a promising imaging-derived biomarker of neurobiological ageing and disease risk, yet current approaches rely predominantly on T1-weighted structural MRI, overlooking functional vascular changes that may precede tissue damage and cognitive decline. DeepCBV maps, synthesized from non-contrast MRI, offer a scalable alternative to contrast-enhanced perfusion imaging by capturing vascular information relevant to early neurodegeneration. We developed a multimodal BrainAGE framework that combines predictions from two separate three-dimensional convolutional neural networks: one trained only on structural MRI scans and another trained only on DeepCBV maps. Each model was trained and validated on 2851 scans from 13 open-source datasets and was evaluated for concordance with MCI and AD. The combined model achieved the most accurate brain age gap for CN controls, with a mean absolute error of 3.95 years, outperforming models trained on MRI or DeepCBV alone. Saliency maps revealed complementary modality contributions: MRI emphasized white matter and cortical atrophy, while DeepCBV highlighted vascular-rich and periventricular regions implicated in hypoperfusion and early cerebrovascular dysfunction, consistent with known patterns of normal ageing. Next, we observed that BrainAGE increased stepwise across diagnostic strata (CN < MCI < AD) and correlated with cognitive impairment. DeepCBV-based BrainAGE showed a particularly strong separation between stable versus progressive MCI, suggesting sensitivity to prodromal vascular changes that precede overt atrophy. Integrating structural MRI with deep learning-derived vascular measures substantially enhances BrainAGE estimation and improves sensitivity to MCI and AD progression, supporting its potential role in risk stratification, early detection and monitoring of therapeutic response.