Mutational signature assignment heterogeneity is widespread and can be addressed by ensemble approaches.

Single-base substitution (SBS) mutational signatures have become standard practice in cancer genomics. In lieu of de novo signature extraction, reference signature assignment allows users to estimate the activities of pre-established SBS signatures within individual malignancies. Several tools have been developed for this purpose, each with differing methodologies. However, due to a lack of standardization, there may be inter-tool variability in signature assignment. We deeply characterized three assignment strategies and five SBS signature assignment tools. We observed that assignment strategy choice can significantly influence results and interpretations. Despite varying recommendations by tools, Refit performed best by reducing overfitting and maximizing reconstruction of the original mutational spectra. Even after uniform application of Refit, tools varied remarkably in signature assignments both qualitatively (Jaccard index = 0.38-0.83) and quantitatively (Kendall tau-b = 0.18-0.76). This phenomenon was exacerbated for 'flat' signatures such as the homologous recombination deficiency signature SBS3. An ensemble approach (EnsembleFit), which leverages output from all five tools, increased SBS3 assignment accuracy in BRCA1/2-deficient breast carcinomas. After generating synthetic mutational profiles for thousands of pan-cancer tumors, EnsembleFit reduced signature activity assignment error 15.9-24.7% on average using Catalogue of Somatic Mutations In Cancer and non-standard reference signature sets. We have also released the EnsembleFit web portal (https://www.ensemblefit.pittlabgenomics.com) for users to generate or download ensemble-based SBS signature assignments using any strategy and combination of tools. Overall, we show that signature assignment heterogeneity across tools and strategies is non-negligible and propose a viable, ensemble solution.

Inpatient rehabilitation outcomes of patients with apraxia after stroke.

BACKGROUND: Stroke-induced paresis commands much attention during rehabilitation; other stroke-related consequences receive less consideration. Apraxia is a stroke disorder that may have important implications for rehabilitation and recovery. OBJECTIVE: To investigate association of apraxia with stroke rehabilitation outcomes during inpatient rehabilitation. METHODS: This cohort study compared patients with and without apraxia after a first left hemispheric stroke. All study patients received standard of care. Clinical measures were the Functional Independence Measure (FIM) and the upper extremity section of the Fugl-Meyer Assessment (FMA) administered upon admission and at discharge. Length of stay was also documented. Florida Apraxia Battery subtests were used to classify patients with apraxia. RESULTS: Fifteen patients were included in this study, 10 of whom had apraxia. Data analysis revealed that patients with apraxia exhibited improvement from admission to discharge in clinical measures; however, admission FIM score was significantly lower compared to patients without apraxia. There was no statistically significant difference between groups on FMA score, length of stay, or amount of change on clinical measures. CONCLUSIONS: This study of acute patients found those with apraxia to be significantly less independent upon admission to inpatient rehabilitation compared to patients without apraxia. Although both groups improved a similar amount during rehabilitation, patients with apraxia discharged at a level of independence comparable to patients without apraxia upon admission. Such disparity in independence is of concern, and apraxia as a factor in stroke rehabilitation and recovery deserves further attention.

Improved function after combined physical and mental practice after stroke: a case of hemiparesis and apraxia.

This study describes change in functional performance and self-perception after participation in combined training with physical practice followed by mental practice. The patient was a 44-yr-old white man who experienced a single left ischemic stroke 7 mo before enrollment in the study. He engaged in physical and mental practice of two functional tasks: (1) reaching for and grasping a cup and (2) turning pages in a book with the more-affected arm. Practice took place 3 times per week during 60-min sessions for 6 consecutive wk. Primary outcome measures were the Arm Motor Ability Test (AMAT) and the Canadian Occupational Performance Measure (COPM). An abbreviated version of the Florida Apraxia Battery gesture-to-verbal command test approximated severity of ideomotor apraxia. After intervention, the patient demonstrated increased functional performance (AMAT) and self-perception of performance (COPM) despite persistent ideomotor apraxia. The results of this single-case report indicate functional benefit from traditional rehabilitation techniques despite comorbid, persisting ideomotor apraxia.

Chronometry of mentally versus physically practiced tasks in people with stroke.

OBJECTIVE: The purpose of this study was to determine whether chronometry is appropriate for monitoring engagement in mental practice by comparing the time taken for people with chronic stroke to mentally and physically practice five tasks. METHOD: Eighteen stroke participants mentally and physically rehearsed each task. Time was recorded for each of the three trials per task. RESULTS: Participants required significantly more time to physically practice than to mentally practice tasks (all p < .05). A significantly greater amount of time for mental practice of the more-affected arm than for the less-affected arm was also observed (p < .01). CONCLUSION: Because there was no agreement between the time taken to mentally and physically practice the tasks, chronometry does not appear to be valid for monitoring mental practice in this population.