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Large longitudinal studies provide lots of valuable information, especially in medical applications. A problem which must be taken care of in order to utilize their full potential is that of correlation between intra-subject measurements taken at different times. For data in Euclidean space this can be done with hierarchical models, that is, models that consider intra-subject and between-subject variability in two different stages. Nevertheless, data from medical studies often takes values in nonlinear manifolds. Here, as a first step, geodesic hierarchical models have been developed that generalize the linear ansatz by assuming that time-induced intra-subject variations occur along a generalized straight line in the manifold. However, this is often not the case (e.g., periodic motion or processes with saturation). We propose a hierarchical model for manifold-valued data that extends this to include trends along higher-order curves, namely B\'ezier splines in the manifold. To this end, we present a principled way of comparing shape trends in terms of a functional-based Riemannian metric. Remarkably, this metric allows efficient, yet simple computations by virtue of a variational time discretization requiring only the solution of regression problems. We validate our model on longitudinal data from the osteoarthritis initiative, including classification of disease progression.

The prevalence of chronic non-communicable diseases such as obesity has noticeably increased in the last decade. The study of these diseases in early life is of paramount importance in determining their course in adult life and in supporting clinical interventions. Recently, attention has been drawn on approaches that study the alteration of metabolic pathways in obese children. In this work, we propose a novel joint modelling approach for the analysis of growth biomarkers and metabolite concentrations, to unveil metabolic pathways related to child obesity. Within a Bayesian framework, we flexibly model the temporal evolution of growth trajectories and metabolic associations through the specification of a joint non-parametric random effect distribution which also allows for clustering of the subjects, thus identifying risk sub-groups. Growth profiles as well as patterns of metabolic associations determine the clustering structure. Inclusion of risk factors is straightforward through the specification of a regression term. We demonstrate the proposed approach on data from the Growing Up in Singapore Towards healthy Outcomes (GUSTO) cohort study, based in Singapore. Posterior inference is obtained via a tailored MCMC algorithm, accommodating a nonparametric prior with mixed support. Our analysis has identified potential key pathways in obese children that allows for exploration of possible molecular mechanisms associated with child obesity.

We study the benign overfitting theory in the prediction of the conditional average treatment effect (CATE), with linear regression models. As the development of machine learning for causal inference, a wide range of large-scale models for causality are gaining attention. One problem is that suspicions have been raised that the large-scale models are prone to overfitting to observations with sample selection, hence the large models may not be suitable for causal prediction. In this study, to resolve the suspicious, we investigate on the validity of causal inference methods for overparameterized models, by applying the recent theory of benign overfitting (Bartlett et al., 2020). Specifically, we consider samples whose distribution switches depending on an assignment rule, and study the prediction of CATE with linear models whose dimension diverges to infinity. We focus on two methods: the T-learner, which based on a difference between separately constructed estimators with each treatment group, and the inverse probability weight (IPW)-learner, which solves another regression problem approximated by a propensity score. In both methods, the estimator consists of interpolators that fit the samples perfectly. As a result, we show that the T-learner fails to achieve the consistency except the random assignment, while the IPW-learner converges the risk to zero if the propensity score is known. This difference stems from that the T-learner is unable to preserve eigenspaces of the covariances, which is necessary for benign overfitting in the overparameterized setting. Our result provides new insights into the usage of causal inference methods in the overparameterizated setting, in particular, doubly robust estimators.

Neurodegenerative diseases are characterized by numerous markers of progression and clinical endpoints. For instance, Multiple System Atrophy (MSA), a rare neurodegenerative synucleinopathy, is characterized by various combinations of progressive autonomic failure and motor dysfunction, and a very poor prognosis. Describing the progression of such complex and multi-dimensional diseases is particularly difficult. One has to simultaneously account for the assessment of multivariate markers over time, the occurrence of clinical endpoints, and a highly suspected heterogeneity between patients. Yet, such description is crucial for understanding the natural history of the disease, staging patients diagnosed with the disease, unraveling subphenotypes, and predicting the prognosis. Through the example of MSA progression, we show how a latent class approach can help describe complex disease progression measured by multiple repeated markers and clinical endpoints, and identify subphenotypes for exploring new pathological hypotheses. The joint latent class model includes class-specific multivariate mixed models to handle multivariate repeated biomarkers possibly summarized into latent dimensions and class-and-cause-specific proportional hazard models to handle time-to-event data. Maximum likelihood estimation is made available in the lcmm R package. In the French MSA cohort comprising data of 598 patients during up to 13 years, five subphenotypes of MSA were identified that differ by the sequence and shape of biomarkers degradation, and the associated risk of death. In posterior analyses, the five subphenotypes were used to explore the association between clinical progression and external imaging and fluid biomarkers, while properly accounting for the uncertainty in the subphenotypes membership.

Statistical analysis is increasingly confronted with complex data from general metric spaces, such as symmetric positive definite matrix-valued data and probability distribution functions. [47] and [17] establish a general paradigm of Fr\'echet regression with complex metric space valued responses and Euclidean predictors. However, their proposed local Fr\'echet regression approach involves nonparametric kernel smoothing and suffers from the curse of dimensionality. To address this issue, we in this paper propose a novel random forests weighted local Fr\'echet regression paradigm. The main mechanism of our approach relies on the adaptive kernels generated by random forests. Our first method utilizes these weights as the local average to solve the Fr\'echet mean, while the second method performs local linear Fr\'echet regression, making both methods locally adaptive. Our proposals significantly improve existing Fr\'echet regression methods. Based on the theory of infinite order U-processes and infinite order Mmn-estimator, we establish the consistency, rate of convergence, and asymptotic normality for our proposed random forests weighted Fr\'echet regression estimator, which covers the current large sample theory of random forests with Euclidean responses as a special case. Numerical studies show the superiority of our proposed two methods for Fr\'echet regression with several commonly encountered types of responses such as probability distribution functions, symmetric positive definite matrices, and sphere data. The practical merits of our proposals are also demonstrated through the application to the human mortality distribution data.

Policy makers typically face the problem of wanting to estimate the long-term effects of novel treatments, while only having historical data of older treatment options. We assume access to a long-term dataset where only past treatments were administered and a short-term dataset where novel treatments have been administered. We propose a surrogate based approach where we assume that the long-term effect is channeled through a multitude of available short-term proxies. Our work combines three major recent techniques in the causal machine learning literature: surrogate indices, dynamic treatment effect estimation and double machine learning, in a unified pipeline. We show that our method is consistent and provides root-n asymptotically normal estimates under a Markovian assumption on the data and the observational policy. We use a data-set from a major corporation that includes customer investments over a three year period to create a semi-synthetic data distribution where the major qualitative properties of the real dataset are preserved. We evaluate the performance of our method and discuss practical challenges of deploying our formal methodology and how to address them.

In a number of application domains, one observes a sequence of network data; for example, repeated measurements between users interactions in social media platforms, financial correlation networks over time, or across subjects, as in multi-subject studies of brain connectivity. One way to analyze such data is by stacking networks into a third-order array or tensor. We propose a principal components analysis (PCA) framework for sequence network data, based on a novel decomposition for semi-symmetric tensors. We derive efficient algorithms for computing our proposed "Coupled CP" decomposition and establish estimation consistency of our approach under an analogue of the spiked covariance model with rates the same as the matrix case up to a logarithmic term. Our framework inherits many of the strengths of classical PCA and is suitable for a wide range of unsupervised learning tasks, including identifying principal networks, isolating meaningful changepoints or outliers across observations, and for characterizing the "variability network" of the most varying edges. Finally, we demonstrate the effectiveness of our proposal on simulated data and on examples from political science and financial economics. The proof techniques used to establish our main consistency results are surprisingly straight-forward and may find use in a variety of other matrix and tensor decomposition problems.

In this study, a longitudinal regression model for covariance matrix outcomes is introduced. The proposal considers a multilevel generalized linear model for regressing covariance matrices on (time-varying) predictors. This model simultaneously identifies covariate associated components from covariance matrices, estimates regression coefficients, and estimates the within-subject variation in the covariance matrices. Optimal estimators are proposed for both low-dimensional and high-dimensional cases by maximizing the (approximated) hierarchical likelihood function and are proved to be asymptotically consistent, where the proposed estimator is the most efficient under the low-dimensional case and achieves the uniformly minimum quadratic loss among all linear combinations of the identity matrix and the sample covariance matrix under the high-dimensional case. Through extensive simulation studies, the proposed approach achieves good performance in identifying the covariate related components and estimating the model parameters. Applying to a longitudinal resting-state fMRI dataset from the Alzheimer's Disease Neuroimaging Initiative (ADNI), the proposed approach identifies brain networks that demonstrate the difference between males and females at different disease stages. The findings are in line with existing knowledge of AD and the method improves the statistical power over the analysis of cross-sectional data.

We study regression adjustments with additional covariates in randomized experiments under covariate-adaptive randomizations (CARs) when subject compliance is imperfect. We develop a regression-adjusted local average treatment effect (LATE) estimator that is proven to improve efficiency in the estimation of LATEs under CARs. Our adjustments can be parametric in linear and nonlinear forms, nonparametric, and high-dimensional. Even when the adjustments are misspecified, our proposed estimator is still consistent and asymptotically normal, and their inference method still achieves the exact asymptotic size under the null. When the adjustments are correctly specified, our estimator achieves the minimum asymptotic variance. When the adjustments are parametrically misspecified, we construct a new estimator which is weakly more efficient than linearly and nonlinearly adjusted estimators, as well as the one without any adjustments. Simulation evidence and empirical application confirm efficiency gains achieved by regression adjustments relative to both the estimator without adjustment and the standard two-stage least squares estimator.

Heatmap-based methods dominate in the field of human pose estimation by modelling the output distribution through likelihood heatmaps. In contrast, regression-based methods are more efficient but suffer from inferior performance. In this work, we explore maximum likelihood estimation (MLE) to develop an efficient and effective regression-based methods. From the perspective of MLE, adopting different regression losses is making different assumptions about the output density function. A density function closer to the true distribution leads to a better regression performance. In light of this, we propose a novel regression paradigm with Residual Log-likelihood Estimation (RLE) to capture the underlying output distribution. Concretely, RLE learns the change of the distribution instead of the unreferenced underlying distribution to facilitate the training process. With the proposed reparameterization design, our method is compatible with off-the-shelf flow models. The proposed method is effective, efficient and flexible. We show its potential in various human pose estimation tasks with comprehensive experiments. Compared to the conventional regression paradigm, regression with RLE bring 12.4 mAP improvement on MSCOCO without any test-time overhead. Moreover, for the first time, especially on multi-person pose estimation, our regression method is superior to the heatmap-based methods. Our code is available at //github.com/Jeff-sjtu/res-loglikelihood-regression