The Joint Effect of Task Similarity and Overparameterization on Catastrophic Forgetting -- An Analytical Model

In continual learning, catastrophic forgetting is affected by multiple aspects of the tasks. Previous works have analyzed separately how forgetting is affected by either task similarity or overparameterization. In contrast, our paper examines how task similarity and overparameterization jointly affect forgetting in an analyzable model. Specifically, we focus on two-task continual linear regression, where the second task is a random orthogonal transformation of an arbitrary first task (an abstraction of random permutation tasks). We derive an exact analytical expression for the expected forgetting - and uncover a nuanced pattern. In highly overparameterized models, intermediate task similarity causes the most forgetting. However, near the interpolation threshold, forgetting decreases monotonically with the expected task similarity. We validate our findings with linear regression on synthetic data, and with neural networks on established permutation task benchmarks.Comment: Accepted to the Twelfth International Conference on Learning Representations (ICLR 2024

Lower Limb Radiology of Distal Myopathy due to the S60F Myotilin Mutation

Distal myopathies are a clinically and genetically heterogenous group of disorders in which the distal limb musculature is selectively or disproportionately affected. Precisely defining specific categories is a challenge because of overlapping clinical phenotypes, making it difficult to decide which of the many known causative genes to screen in individual cases. In this study we define the distinguishing magnetic resonance imaging findings in myotilin myopathy by studying 8 genealogically unrelated cases due to the same point mutation in TTID. Proximally, the vastii, biceps femoris and semimembranosus were involved with sparing of gracilis and sartorius. Distally, soleus, gastrocnemius, tibialis anterior, extensor hallicus and extensor digitorum were involved. This pattern contrasts with other distal myopathies and provides further support for the role of imaging in the clinical investigation of muscle disease. Copyright (C) 2009 S. Karger AG, Base

Investigations on influenza A virus morphology

Clinical isolates of influenza A virus (IAV) typically form a pleomorphic population of virions that present as a continuum of morphologies broadly classified as filaments, bacilli, and spheres. Laboratory strains of IAV, however present mainly as spherical and bacilliform particles, suggesting a role for filaments in vivo. How these filaments form is not fully understood, but it has previously been shown that mutations in the viral matrix protein (M1) can be determinants of filament formation. In this work we show that filament formation also depends on multiple other genetic factors. To this end, we compared two IAV strains A/equine/Ohio/03 (O/2003) and A/equine/South Africa/4/03 (SA/2003) and found that SA/2003 could form filaments while O/2003 could not, despite no differences in their M1 sequences. To map the genetic basis of this difference, we generated reassortant viruses between O/2003 and SA/2003 and identified segments 1 (encoding polymerase basic protein 2, PB2), 4 (haemagglutinin, HA) and 6 (neuraminidase, NA) as determinants of morphology. We established that single mutations in segments 4 and 6, which alter the HA and NA proteins, alter virion morphology. To our surprise, we also identified three synonymous mutations in segment 1 of the virus that were determinants of filament formation despite not altering any known protein. We then extended this work to unravel the associated mechanisms of this change and found despite some differences in the activity of NA, contribution of HA to filament production, and differences in segment 1 RNA structure, there was no clear underlying mechanism. Given, that we were unable to identify the mechanisms associated with the change in morphology, we further extended this work to identify the factors involved in morphogenesis. To characterize IAV filament morphogenesis we employed cryogenic electron tomography (Cryo-ET) of vitrified equine fibroblasts (E. Derm). Although we were unable to identify any additional factors associated with IAV budding, we were able to generate a robust pipeline for studying filament formation. These results show that M1 is not the only determinant of IAV morphology, and that the ability to form filaments, a poorly studied but natural characteristic of IAV infection, is in fact modulated by multiple proteins and RNA determinants

Simulations of Oligomeric Intermediates in Prion Diseases

We extend our previous stochastic cellular automata based model for areal aggregation of prion proteins on neuronal surfaces. The new anisotropic model allow us to simulate both strong beta-sheet and weaker attachment bonds between proteins. Constraining binding directions allows us to generate aggregate structures with the hexagonal lattice symmetry found in recently observed in vitro experiments. We argue that these constraints on rules may correspond to underlying steric constraints on the aggregation process. We find that monomer dominated growth of the areal aggregate is too slow to account for some observed doubling time-to-incubation time ratios inferred from data, and so consider aggregation dominated by relatively stable but non-infectious oligomeric intermediates. We compare a kinetic theory analysis of oligomeric aggregation to spatially explicit simulations of the process. We find that with suitable rules for misfolding of oligomers, possibly due to water exclusion by the surrounding aggregate, the resulting oligomeric aggregation model maps onto our previous monomer aggregation model. Therefore it can produce some of the same attractive features for the description of prion incubation time data. We propose experiments to test the oligomeric aggregation model.Comment: 8 pages, 10 figures For larger versions of several figures, see http://asaph.ucdavis.edu/~dmobley and click on the prion paper lin

Ferric Gluconate Yields Cost-Savings in Hemodialysis Patients with High Ferritin and Low TSAT: Results from the DRIVE Studies

Purpose: One third of hemodialysis patients have high serum ferritin levels and low transferrin saturation (TSAT). The purpose of this analysis was to determine the cost effectiveness of administering 1g of sodium ferric gluconate complex (SFGC: also referred to as ferric gluconate) to patients with serum ferritin \u3e500ng/mL and TSAT ≤25% based on the Dialysis Patients Response to IV Iron with Elevated Ferritin (DRIVE) study and its 6-week observational extension (DRIVE-II). In these studies, IV iron administration resulted in reduced epoetin requirements. Methods: Decision analysis was performed using a time horizon of 12 weeks, consistent with the combined duration of DRIVE and DRIVE II. Treatment effectiveness was based on mean increase in hemoglobin (Hb) for each group (SFGC plus epoetin or epoetin alone) in the intention to treat populations. Costs included drugs (SFGC and epoetin) and hospitalizations due to serious adverse events (SAEs) reported. The primary cost effectiveness measure was cost per g/dL of Hb increase at 12 weeks. Costs were computed from a Medicare perspective using projected 2007 reimbursements. Sensitivity analyses were performed to test the impact of using the safety population, median epoetin and SFGC doses, actual 2005 Medicare reimbursements, median increases in Hb, and SAE rate changes. The model was constructed using TreeAge Pro software. Results: Total cost per patient receiving SFGC plus epoetin was $3675 per g/dL Hb increase, while the total cost per patient receiving epoetin alone was$5065 per g/dL Hb increase. Net savings for SFGC plus epoetin was $1390 per g/dL Hb increase over the 12 week period Sensitivity analyses affirmed the robustness of the model. Conclusion: Administering 1g of SFGC plus epoetin in patients with high ferritin and low TSAT as defined in the DRIVE studies resulted in significant cost-savings compared to epoetin alone