Generalized expectile regression with flexible response function.

Expectile regression, in contrast to classical linear regression, allows for heteroscedasticity and omits a parametric specification of the underlying distribution. This model class can be seen as a quantile-like generalization of least squares regression. Similarly as in quantile regression, the whole distribution can be modeled with expectiles, while still offering the same flexibility in the use of semiparametric predictors as modern mean regression. However, even with no parametric assumption for the distribution of the response in expectile regression, the model is still constructed with a linear relationship between the fitted value and the predictor. If the true underlying relationship is nonlinear then severe biases can be observed in the parameter estimates as well as in quantities derived from them such as model predictions. We observed this problem during the analysis of the distribution of a self-reported hearing score with limited range. Classical expectile regression should in theory adhere to these constraints, however, we observed predictions that exceeded the maximum score. We propose to include a response function between the fitted value and the predictor similarly as in generalized linear models. However, including a fixed response function would imply an assumption on the shape of the underlying distribution function. Such assumptions would be counterintuitive in expectile regression. Therefore, we propose to estimate the response function jointly with the covariate effects. We design the response function as a monotonically increasing P-spline, which may also contain constraints on the target set. This results in valid estimates for a self-reported listening effort score through nonlinear estimates of the response function. We observed strong associations with the speech reception threshold.

Optimizing Refractive Outcomes of SMILE: Artificial Intelligence versus Conventional State-of-the-Art Nomograms.

PURPOSE: AI (artificial intelligence)-based methodologies have become established tools for researchers and physicians in the entire field of ophthalmology. However, the potential of AI to optimize the refractive outcome of keratorefractive surgery by means of machine learning (ML)-based nomograms has not been exhausted yet. In this study, we wanted to comprehensively compare state-of-the-art conventional nomograms for Small-Incision-Lenticule-Extraction (SMILE) with a novel ML-based nomogram regarding both their spherical and astigmatic predictability. METHODS: A total of 1,342 eyes were analyzed for creation of three different nomograms based on a linear model (LM), a generalized additive mixed model (GAMM) and an artificial-neuronal-network (ANN), respectively. A total of 16 patient- and treatment-related features were included. Each model was trained by 895 eyes and validated by the remaining 447 eyes. Predictability was assessed by the difference between attempted and achieved change in spherical equivalent (SE) and the difference between target induced astigmatism (TIA) and surgically induced astigmatism (SIA). The root mean squared error (RMSE) of each model was computed as a measure of overall model performance. RESULTS: The RMSE of LM, GAMM and ANN were 0.355, 0.348 and 0.367 for the prediction of SE and 0.279, 0.278 and 0.290 for the astigmatic correction, respectively. By applying the created models, the theoretical yield of eyes within ±0.50 D of SE from target refraction improved from 82 to 83% (LM), 84% (GAMM) and 83% (ANN), respectively. Astigmatic outcomes showed an improvement of eyes within ±0.50 D from TIA from 90 to 93% (LM), 93% (GAMM) and 92% (ANN), respectively. Subjective manifest refraction was the single most influential covariate in all models. CONCLUSION: Machine learning endorsed the validity of state-of-the-art linear and non-linear SMILE nomograms. However, improving the accuracy of subjective manifest refraction seems warranted for optimizing ±0.50 D SE predictability beyond an apparent methodological 90% limit.

Identification of Intrinsic Drug Resistance and Its Biomarkers in High-Throughput Pharmacogenomic and CRISPR Screens.

High-throughput drug screens in cancer cell lines test compounds at low concentrations, thereby enabling the identification of drug-sensitivity biomarkers, while resistance biomarkers remain underexplored. Dissecting meaningful drug responses at high concentrations is challenging due to cytotoxicity, i.e., off-target effects, thus limiting resistance biomarker discovery to frequently mutated cancer genes. To address this, we interrogate subpopulations carrying sensitivity biomarkers and consecutively investigate unexpectedly resistant (UNRES) cell lines for unique genetic alterations that may drive resistance. By analyzing the GDSC and CTRP datasets, we find 53 and 35 UNRES cases, respectively. For 24 and 28 of them, we highlight putative resistance biomarkers. We find clinically relevant cases such as EGFRT790M mutation in NCI-H1975 or PTEN loss in NCI-H1650 cells, in lung adenocarcinoma treated with EGFR inhibitors. Interrogating the underpinnings of drug resistance with publicly available CRISPR phenotypic assays assists in prioritizing resistance drivers, offering hypotheses for drug combinations.