Neural Posterior Estimation

Augmenting small concurrent studies with external or historical cohorts is attractive in drug development, where enrollment is slow, follow-up is expensive, and closely related trial or real-world data are often already available. Bayesian dynamic borrowing (BDB) provides a principled framework for adaptively controlling the influence of external data, but classical implementations often depend on hand-specified priors and MCMC-based inference, which can be computationally expensive and not generalizable. In this work, we study amortized neural posterior estimation (NPE) as a flexible alternative. A single network is pretrained on simulated current/external dataset pairs spanning covariate shift, outcome drift, and joint non-exchangeability, and then returns an approximate posterior for a scalar current-study target in a single forward pass. Through simulation studies, we find that NPE is most useful under outcome drift and joint mismatch: in the harder outcome-drift regimes, it gives up to about five-fold lower absolute bias than the best classical baseline and keeps Type I error close to nominal. After pretraining, posterior summaries are obtained in about 8 ms per dataset, roughly $10^3\times$ faster than MCMC-based borrowing baselines in our timing experiment. We further analyze Alzheimer's Disease Neuroimaging Initiative (ADNI) data and show that, when mild cognitive impairment outcomes differ across cohorts, the NPE formulation recovers the later-cohort risk level in this example without claiming greater precision. Code is available at https://github.com/ChinHungScott/NPE-for-Bayesian-Dynamic-Borrowing-MLHC-.

Clinical scalp electroencephalography (EEG) offers a noninvasive window into neural dynamics of neuropsychiatric disorders. However, discriminative deep models often lack anatomically indexed physiological interpretability. We propose NeuroDyn-EEG, a pretraining framework integrating generative priors from neural dynamics. It couples an extended Jansen-Rit neural mass model, leadfield-based source projection, and simulation-based parameter inversion. Trained on synthetic parameter-EEG pairs within physiological ranges, NeuroDyn-EEG estimates 11 regional parameter families across 90 AAL regions plus one global parameter from standard 19-channel EEG, using only ~2.43M trainable parameters. We evaluate the framework across three levels. First, controlled simulations demonstrate robust parameter recovery under diverse noise conditions, while real resting-state EEG evaluations confirm spectral and phase consistency in an inverse-forward closed loop. Second, on four clinical benchmarks (AD65, PD31, Figshare MDD, and TUAB), NeuroDyn-EEG achieves competitive classification performance, securing the highest BACC, AUROC, and AUCPR on PD31 and MDD, and highest BACC on AD65. Third, post hoc regional analyses reveal disease-specific alterations: local synaptic connectivity C_1 involves the most altered regions in AD65, whereas the firing threshold theta ranks first in MDD, offering testable mechanistic hypotheses. Overall, NeuroDyn-EEG maps scalp EEG to anatomically indexed dynamical parameters, bridging representation learning and mechanistic neurophysiology. Code: https://github.com/Gnosis-Neurodynamics/NeuroDyn-EEG.

Models of quantum systems faithfully map system parameters to observations, but the inverse problem of parameter inference from measurement data presents a fundamental challenge: computationally intractable likelihoods due to an exponentially large Hilbert space. Here, we introduce simulation-based quantum system inference, a unified, likelihood-free framework that learns parameter posteriors directly from classical simulation data. The central idea is to pair polynomial-cost classical simulators, such as Pauli propagation and tensor networks, with normalizing flows or other neural density estimators for accurate, reusable inference. A single model, trained once, maps any new measurement record to its posterior in one forward pass---turning per-experiment inference into a fixed, up-front cost. We numerically demonstrate the framework's versatility across Pauli noise learning, quantum error mitigation, quantum state tomography, and Hamiltonian learning, with examples involving 81-qubit shallow circuits and 735-parameter inference. In each case, the approach yields accurate estimates of identifiable parameters, while posterior uncertainty provides additional diagnostics of non-identifiability and indicates where further characterization is needed. Our framework reduces data-acquisition requirements in quantum experiments and accelerates parameter inference, providing a practical route to characterizing and improving large-scale quantum systems.

Hierarchical data is ubiquitous in the empirical sciences and is most commonly analyzed with generalized linear mixed-effects models (GLMMs). Bayesian inference for GLMMs yields calibrated uncertainty but requires MCMC; the No-U-Turn Sampler (NUTS) is the gold standard but is slow and must restart from scratch for every new dataset, model and prior. We introduce metabeta, a pretrained neural network for prior-amortized in-context Bayesian inference over GLMMs. Unlike previous neural posterior estimators that fix the prior at training time, metabeta accepts prior families and hyperparameters as inputs at test time, enabling zero-shot generalization. Two set transformers and conditional normalizing flows mirror the posterior's two-level structure (global parameters shared across groups, local parameters per group). The model is trained on millions of realistic simulated datasets spanning continuous, binary, and count outcomes. By default, the flow posterior is refined by Independence Metropolis-Hastings against the unnormalized posterior, so its correctness rests on the sampler rather than the network; this yields tuning-free inference two to three orders of magnitude faster than NUTS. Alternatively, the flow can warm-start NUTS, giving nearly identical inference with substantially increased speed and stability. On controlled benchmarks with ground-truth parameters, metabeta matches NUTS in parameter recovery, calibration and out-of-sample prediction. On out-of-distribution real datasets, its posteriors closely match those of NUTS across all parameter types, and they remain faithful under misspecified likelihoods and priors, out-of-distribution predictors, collinear designs, and data-poor regimes. The model is open-source and open-weights and thus immediately deployable.

Robots that localize a radio transmitter need more than a point estimate: in cluttered rooms, one measurement is often consistent with several transmitter locations and, because upper-mid-band antennas are directional, several headings. We present MAGNETAR, which infers a joint posterior over planar transmitter position and heading from a single asynchronous radio-frequency (RF) multipath snapshot, represented by angle-of-arrival and signal-to-noise-ratio estimates, given the room layout and receiver pose. Among our five neural scorers, MAGNETAR adopts a shared 2D U-Net conditioned on each candidate heading, jointly normalizing scores over a discretized position-heading grid. Training uses real-to-sim-calibrated 10 GHz simulations and a small measured subset. Grid-based joint posteriors outperform parametric ones on held-out simulations, the heading-conditioned scorer transfers best to robotic measurements, and fusing joint posteriors improves on fusing position-only marginals.

Weak gravitational lensing shear and convergence trace the distribution of baryonic and dark matter across space, making them a powerful probe of cosmic structure. Inferring shear and convergence from images is a challenging inverse problem. The prevailing approach to this task estimates shear from weighted averages of galaxy ellipticities, calibrates these estimates to account for systematic biases, and transforms them to reconstruct convergence, a multistage procedure that requires substantial computational resources and meticulous handling of statistical uncertainties. As an alternative, we propose a probabilistic approach to field-level weak lensing inference in which we train a deep neural network to directly map a multiband image to a variational distribution over the underlying tomographic shear and convergence fields. This neural posterior estimation (NPE) procedure implicitly marginalizes over nuisance variables in the cosmological forward model and does not require evaluating the likelihood function. It is also amortized, so it enables rapid posterior inference for astronomical surveys once the neural network is trained. When evaluated on synthetic images from the LSST-DESC DC2 Simulated Sky Survey, NPE produces well-calibrated variational distributions for shear and convergence that are consistent with the ground truth. We describe how maps sampled from these variational distributions could be used in a subsequent simulation-based inference procedure to approximate the posterior distribution over cosmological parameters.

The drift diffusion model (DDM) is a cornerstone of cognitive decision-making research. Although numerous estimation methods exist, researchers continue to seek inference approaches that are both fast and flexible across diverse study designs. Amortized Bayesian inference (ABI) can provide nearly instantaneous inference for complex stochastic models like the DDM, but neural networks trained for one study design cannot generalize to others. In this paper, we propose a divide-and-conquer framework that address this limitation. The core idea is that the DDM's independence assumption allows the full dataset to be decomposed into pairwise shards, each sharing a common structure that a single neural network can learn. Inference is performed on each shard separately and the resulting posteriors are combined via consensus MCMC to approximate the full posterior. Using simulated datasets, we evaluate the accuracy and uncertainty of this method. Our results show that the proposed divide-and-conquer approach achieves accuracy and uncertainty comparable to MCMC while reducing computational cost by several orders of magnitude. This work not only advances DDM estimation but also demonstrates a general strategy for improving the scalability and generalizability of ABI methods across diverse applications.

Simulation-based inference (SBI) with machine learning is an increasingly important tool for solving inverse problems in science and engineering, including parameter inference and the inversion of detector effects. We provide an overview of the Bayesian and frequentist statistical frameworks, describe how machine-learning-based SBI methods, such as neural posterior estimation and neural likelihood estimation, can be used for parameter estimation within these frameworks, and show that the same methods can also be applied to Empirical Bayes or unfolding tasks. We also discuss how to validate inference results and the limitations of SBI with machine learning.

The prevailing approach to inferring weak gravitational lensing shear from images involves detecting galaxies, estimating their ellipticities, and calibrating these estimates to correct for image noise, selection bias, and model misspecification. Characterizing the statistical model and assumptions underlying this pipeline is challenging, which makes it difficult to propagate uncertainty through its various stages. As an alternative, we propose to infer shear using neural posterior estimation (NPE), a type of simulation-based inference. We train a deep neural network to map a simulated multiband image to a variational distribution over the underlying shear field, thereby folding galaxy detection, deblending, measurement, and calibration into a single implicit inference step. Once trained, the network accounts for all features present in the simulated images, including potential sources of bias. In experiments on simulated constant-shear images with increasingly complex observational effects, NPE produces accurate and well-calibrated posterior approximations for both shear components in the presence of blended galaxies, spatially varying point spread functions, stars, and detector artifacts. These results demonstrate that NPE can be a viable shear estimation method in settings where all anticipated features and artifacts can be simulated, a requirement that will become increasingly feasible as simulation fidelity improves in the coming decades.

Mechanistic epidemiological models are widely used to support infectious disease forecasting and public-health decision making. Bayesian calibration of such models is commonly performed using Markov chain Monte Carlo (MCMC), which can become computationally expensive for high-dimensional nonlinear systems and repeated near-real-time analyses. Here, we investigate simulation-based inference (SBI) using neural posterior estimation as a scalable alternative for Bayesian calibration of a mechanistic SECIR epidemiological model using COVID-19 intensive care unit (ICU) occupancy data from Germany during 2020. We compared SBI and MCMC across multiple epidemic phases using both 31-day inference windows and a substantially more challenging 201-day reconstruction problem involving multiple transmission change points. Posterior agreement was evaluated quantitatively using Wasserstein distances and Kullback-Leibler divergences together with posterior predictive checks. Across the 31-day windows, SBI recovered posterior distributions in strong agreement with MCMC while accurately reproducing observed ICU trajectories. In the 201-day setting, SBI preserved the dominant posterior structure despite increased uncertainty. SBI, by combining CPU and GPU resources, substantially reduced computational runtime compared with MCMC, which was restricted to running on CPUs. Whereas MCMC required approximately 1000 seconds for the 31-day inference problems, SBI achieved comparable posterior and predictive performance in approximately 60-70 seconds on a single GPU. For the 201-day inference problem, SBI required an average of 157 seconds, while the MCMC runs took over 19,000 seconds. Our results demonstrate that SBI provides a rapid and computationally efficient framework for Bayesian calibration of mechanistic epidemiological models, supporting repeated near-real-time inference and rapid outbreak analysis.

Structured weight-uncertainty can improve many aspects of deep learning, but it remains costly to estimate and difficult to implement. Here, we show that these issues can be addressed by adapting the SOAP optimizer. Our key idea is to run IVON, an existing diagonal-covariance variational method, in the eigenspace of SOAP's preconditioner and then use the preconditioner to transform the diagonal estimate into a non-diagonal covariance. The resulting method has costs similar to those of SOAP and requires no drastic changes to training pipelines. We call the posteriors obtained in this way SOAP-Bubbles and our new optimizer Eigenspace-VON (EVON). We show that, for logistic regression, EVON recovers the exact Gaussian covariance and that, for language model pretraining, it yields significantly better results than existing diagonal-covariance methods. Our work makes it easier to estimate more expressive posterior distributions for deep learning at scale.

Simulation-based inference with neural posterior estimation (NPE) often yields overconfident and unreliable posteriors under limited simulation budgets. To address this, we propose DRO-NPE, a distributionally robust approach that replaces the standard NPE objective with a worst-case loss over a Wasserstein ambiguity set. We introduce KL-based metrics for miscoverage and miscalibration, and use these to show that the DRO-NPE objective controls overfitting and reduces posterior overconfidence. Our method is tractable, parallelisable, and readily integrates with standard normalising flows. Across benchmark SBI tasks, DRO-NPE consistently improves coverage and calibration, while narrowing the gap between empirical and population NPE loss, leading to more reliable inference in low-simulation regimes.

Flow and diffusion generative models have established themselves as widely adopted density estimators for simulation-based inference (SBI), extending naturally from neural posterior estimation to likelihood and joint density estimation. Their principled optimization objectives and freedom from architectural constraints have driven rapid adoption across the natural sciences. Yet the most widely used SBI libraries remain PyTorch-based, leaving researchers who develop their forward models and analysis pipelines in JAX without a native option. We present GenSBI, an open-source library that implements flow matching, score matching, and denoising diffusion entirely in JAX. The library offers three transformer-based architectures - SimFormer, Flux1, and a novel Flux1Joint that extends gate-modulated transformer blocks to joint density estimation - all interchangeable through a unified interface that decouples generative method, neural backbone, and inference mode. GenSBI provides an end-to-end workflow from training through posterior calibration (SBC, TARP, LC2ST) and supports custom architectures with domain-specific embedding networks. We validate the framework on standard SBI benchmarks, achieving near-ideal mean C2ST scores (0.50-0.56, where 0.50 is ideal) on SBIBM tasks with minimal per-task tuning and well-calibrated posterior coverage across all tested configurations. The code is publicly available at https://github.com/aurelio-amerio/GenSBI.

Neural Posterior Estimation (NPE) enables rapid parameter inference for complex simulators with intractable likelihoods. NPE trains an inference network to estimate a probability density over parameters given data, typically assumed to be \emph{continuous}. However, many scientific models involve parameter spaces that are \emph{mixed}, that is, they contain both discrete and continuous dimensions. We address this limitation by extending NPE to mixed parameter spaces through an inference network that jointly handles discrete and continuous parameters. The inference network factorizes the joint posterior into discrete and continuous components, combining an autoregressive classifier for the discrete parameters with a generative model for the continuous parameters, trained jointly under a single simulation-based objective. In addition, we propose a diagnostic tool to assess the calibration of the mixed posterior approximation. Across tractable toy examples and real-world scientific simulators, our joint inference approach yields accurate and calibrated posteriors. The inference framework is available in the \texttt{sbi} Python package.

Neural posterior estimation has emerged as a powerful tool for amortized inference, with growing adoption across scientific and applied domains. In many of these applications, the conditioning variable is a set of observations whose elements depend not only on the target but also on unknown factors shared across the set. Optimal inference therefore requires treating the set jointly, which in turn requires training the estimator at the deployment set size -- a regime where memory and compute quickly become prohibitive. We introduce a simple, theoretically grounded strategy that decouples representation learning from posterior modeling. Our method trains a mean-pool Deep Set on sets of size at most two, producing an encoder that generalizes to arbitrary set sizes. The inference head is then finetuned on pre-aggregated embeddings, making training cost essentially independent of the deployment set size N. Across scalar, image, multi-view 3D, molecular, and high-dimensional conditional generation benchmarks with N in the thousands, our approach matches or outperforms standard baselines at a fraction of the compute.

In this work, we study TabPFN as a training-free, modular summary network for simulation-based Bayesian inference (SBI). Tabular foundation models such as TabPFN are pretrained on broad families of synthetic tabular data-generating processes and adapt at test time through in-context learning, making them natural candidates for SBI, where posterior estimation often depends on learning informative summaries of simulated observations. We propose PFN-NPE: a general recipe that uses a pretrained TabPFN encoder as a fixed summary network for simulator outputs, then pairs the resulting summaries with a downstream inference head chosen for the problem. With normalizing flows as the default inference head, PFN-NPE matches established posterior approximation methods and sometimes outperforms them. More importantly, diagnostic probes show that the TabPFN-derived summaries often preserve useful posterior location and marginal information. These analyses also reveal a limitation in that TabPFN-derived summaries may struggle to represent the joint posterior structure even when the marginals are well recovered. Still, our experiments show that TabPFN can serve as an effective summary network across a diverse set of SBI settings, with the inference network left modular and task-dependent.

Radar sounders are electromagnetic instruments that can probe deep into the subsurface of Earth and other planetary bodies by processing the echo of transmitted radar waves. Conventional approaches for analyzing such data rely on approximate assumptions and often produce point estimates that ignore parameter correlations as well as galactic and measurement noise. We propose a simulation-based inference approach to terrain parameter inversion from radar sounder data, where synthetic observations from a GPU-based simulator are used to train a neural network-based density estimator for neural posterior estimation (NPE). By explicitly conditioning on reference surface assumptions, the proposed framework allows systematic evaluation of posterior robustness to reference surface variability. We demonstrate that our NPE model is well calibrated on simulated data and transferable to real Mars radar profiles, where we analyze terrain parameters using literature-informed reference values.

Quantitative imaging methods, such as magnetic resonance fingerprinting (MRF), aim to extract interpretable pathology biomarkers by estimating biophysical tissue parameters from signal evolutions. However, the pattern-matching algorithms or neural networks used in such inverse problems often lack principled uncertainty quantification, which limits the trustworthiness and transparency, required for clinical acceptance. Here, we describe a physics-structured variational autoencoder (PS-VAE) designed for rapid extraction of voxelwise multi-parameter posterior distributions. Our approach integrates a differentiable spin physics simulator with self-supervised learning, and provides a full covariance that captures the inter-parameter correlations of the latent biophysical space. The method was validated in a multi-proton pool chemical exchange saturation transfer (CEST) and semisolid magnetization transfer (MT) molecular MRF study, across in-vitro phantoms, tumor-bearing mice, healthy human volunteers, and a subject with glioblastoma. The resulting multi-parametric posteriors are in good agreement with those calculated using a brute-force Bayesian analysis, while providing an orders-of-magnitude acceleration in whole brain quantification. In addition, we demonstrate how monitoring the multi-parameter posterior dynamics across progressively acquired signals provides practical insights for protocol optimization and may facilitate real-time adaptive acquisition.

We present Causal Posterior Estimation (CPE), a novel method for Bayesian inference in simulator models, where evaluating the likelihood function is intractable or computationally expensive, but generating outputs given parameter values is straightforward. CPE approximates the posterior distribution using flow matching while directly incorporating the conditional dependence structure induced by the model's graphical representation into the neural network architecture. Across extensive experiments, we demonstrate that hard-coding these conditional dependencies into the network, rather than requiring them to be learned from data, enables CPE to achieve highly accurate posterior inference that matches or outperforms state-of-the-art baselines.