Background Ineffective drug treatment is a major problem for many patients with immune-mediated inflammatory diseases (IMIDs). Important reasons are the lack of systematic solutions for drug prioritisation and repurposing based on characterisation of the complex and heterogeneous cellular and molecular changes in IMIDs.Methods Here, we propose a computational framework, scDrugPrio, which constructs network models of inflammatory disease based on single-cell RNA sequencing (scRNA-seq) data. scDrugPrio constructs detailed network models of inflammatory diseases that integrate information on cell type-specific expression changes, altered cellular crosstalk and pharmacological properties for the selection and ranking of thousands of drugs.Results scDrugPrio was developed using a mouse model of antigen-induced arthritis and validated by improved precision/recall for approved drugs, as well as extensive in vitro, in vivo, and in silico studies of drugs that were predicted, but not approved, for the studied diseases. Next, scDrugPrio was applied to multiple sclerosis, Crohn's disease, and psoriatic arthritis, further supporting scDrugPrio through prioritisation of relevant and approved drugs. However, in contrast to the mouse model of arthritis, great interindividual cellular and gene expression differences were found in patients with the same diagnosis. Such differences could explain why some patients did or did not respond to treatment. This explanation was supported by the application of scDrugPrio to scRNA-seq data from eleven individual Crohn's disease patients. The analysis showed great variations in drug predictions between patients, for example, assigning a high rank to anti-TNF treatment in a responder and a low rank in a nonresponder to that treatment.Conclusions We propose a computational framework, scDrugPrio, for drug prioritisation based on scRNA-seq of IMID disease. Application to individual patients indicates scDrugPrio's potential for personalised network-based drug screening on cellulome-, genome-, and drugome-wide scales. For this purpose, we made scDrugPrio into an easy-to-use R package (https://github.com/SDTC-CPMed/scDrugPrio).

Recent technical developments and early clinical examples support that precision medicine has potential to provide novel diagnostic and therapeutic solutions for patients with complex diseases, who are not responding to existing therapies. Those solutions will require integration of genomic data with routine clinical, imaging, sensor, biobank and registry data. Moreover, user-friendly tools for informed decision support for both patients and clinicians will be needed. While this will entail huge technical, ethical, societal and regulatory challenges, it may contribute to transforming and improving health care towards becoming predictive, preventive, personalised and participatory (4P-medicine).

Ett av de största problemen för många patienter är attde inte förbättras av läkemedelsbehandling. Detta orsakar, förutom lidande, stora samhällskostnader. Viktigaorsaker är sjukdomars molekylära komplexitet samt sendiagnostik och behandling.

Precisionsmedicin kan bidra till att lösa problem genom att karakterisera och tolka denna komplexitet. Ettexempel är att läkemedelsbehandling kan provas ut ochindividualiseras genom datorsimuleringar.

Precisionsmedicin har potential att påtagligt förbättrabåde hälsa och ekonomi. Detta kräver en bred IT-strategi för att integrera genomik- och andra storskaligadatakällor, som inkluderar nationella superdator-,visualiserings- och AI-centrum.

Monotonic regression is a standard method for extracting a monotone function from non-monotonic data, and it is used in many applications. However, a known drawback of this method is that its fitted response is a piecewise constant function, while practical response functions are often required to be continuous. The method proposed in this paper achieves monotonicity and smoothness of the regression by introducing an L₂ regularization term. In order to achieve a low computational complexity and at the same time to provide a high predictive power of the method, we introduce a probabilistically motivated approach for selecting the regularization parameters. In addition, we present a technique for correcting inconsistencies on the boundary. We show that the complexity of the proposed method is O(n²). Our simulations demonstrate that when the data are large and the expected response is a complicated function (which is typical in machine learning applications) or when there is a change point in the response, the proposed method has a higher predictive power than many of the existing methods.

Personalized medicine aims at identifying best treatments for a patient with given characteristics. It has been shown in the literature that these methods can lead to great improvements in medicine compared to traditional methods prescribing the same treatment to all patients. Subgroup identification is a branch of personalized medicine, which aims at finding subgroups of the patients with similar characteristics for which some of the investigated treatments have a better effect than the other treatments. A number of approaches based on decision trees have been proposed to identify such subgroups, but most of them focus on two‐arm trials (control/treatment) while a few methods consider quantitative treatments (defined by the dose). However, no subgroup identification method exists that can predict the best treatments in a scenario with a categorical set of treatments. We propose a novel method for subgroup identification in categorical treatment scenarios. This method outputs a decision tree showing the probabilities of a given treatment being the best for a given group of patients as well as labels showing the possible best treatments. The method is implemented in an R package psica available on CRAN. In addition to a simulation study, we present an analysis of a community‐based nutrition intervention trial that justifies the validity of our method.

In many problems, it is necessary to take into account monotonic relations. Monotonic (isotonic) Regression (MR) is often involved in solving such problems. The MR solutions are of a step-shaped form with a typical sharp change of values between adjacent steps. This, in some applications, is regarded as a disadvantage. We recently introduced a Smoothed MR (SMR) problem which is obtained from the MR by adding a regularization penalty term. The SMR is aimed at smoothing the aforementioned sharp change. Moreover, its solution has a far less pronounced step-structure, if at all available. The purpose of this paper is to further improve the SMR solution by getting rid of such a structure. This is achieved by introducing a lowed bound on the slope in the SMR. We call it Smoothed Slope-Constrained MR (SSCMR) problem. It is shown here how to reduce it to the SMR which is a convex quadratic optimization problem. The Smoothed Pool Adjacent Violators (SPAV) algorithm developed in our recent publications for solving the SMR problem is adapted here to solving the SSCMR problem. This algorithm belongs to the class of dual active-set algorithms. Although the complexity of the SPAV algorithm is o(n²) its running time is growing in our computational experiments almost linearly with n. We present numerical results which illustrate the predictive performance quality of our approach. They also show that the SSCMR solution is free of the undesirable features of the MR and SMR solutions.

Monotonic Regression (MR) is a standard method for extracting a monotone function from non-monotonic data, and it is used in many applications. However, a known drawback of this method is that its fitted response is a piecewise constant function, while practical response functions are often required to be continuous. The method proposed in this paper achieves monotonicity and smoothness of the regression by introducing an L2 regularization term, and it is shown that the complexity of this method is O(n²). In addition, our simulations demonstrate that the proposed method normally has higher predictive power than some commonly used alternative methods, such as monotonic kernel smoothers. In contrast to these methods, our approach is probabilistically motivated and has connections to Bayesian modeling.

It is sometimes the case that a theory proposes that the population means on two variables should have the same rank order across a set of experimental conditions. This paper presents a test of this hypothesis. The test statistic is based on the coupled monotonic regression algorithm developed by the authors. The significance of the test statistic is determined by comparison to an empirical distribution specific to each case, obtained via non-parametric or semi-parametric bootstrap. We present an analysis of the power and Type I error control of the test based on numerical simulation. Partial order constraints placed on the variables may sometimes be theoretically justified. These constraints are easily incorporated into the computation of the test statistic and are shown to have substantial effects on power. The test can be applied to any form of data, as long as an appropriate statistical model can be specified.

Recently, the methods used to estimate monotonic regression (MR) models have been substantially improved, and some algorithms can now produce high-accuracy monotonic fits to multivariate datasets containing over a million observations. Nevertheless, the computational burden can be prohibitively large for resampling techniques in which numerous datasets are processed independently of each other. Here, we present efficient algorithms for estimation of confidence limits in large-scale settings that take into account the similarity of the bootstrap or jackknifed datasets to which MR models are fitted. In addition, we introduce modifications that substantially improve the accuracy of MR solutions for binary response variables. The performance of our algorithms isillustrated using data on death in coronary heart disease for a large population. This example also illustrates that MR can be a valuable complement to logistic regression.

Monotonic (isotonic) Regression (MR) is a powerful tool used for solving a wide range of important applied problems. One of its features, which poses a limitation on its use in some areas, is that it produces a piecewise constant fitted response. For smoothing the fitted response, we introduce a regularization term in the MR formulated as a least distance problem with monotonicity constraints. The resulting Smoothed Monotonic Regrassion (SMR) is a convex quadratic optimization problem. We focus on the SMR, where the set of observations is completely (linearly) ordered. Our Smoothed Pool-Adjacent-Violators (SPAV) algorithm is designed for solving the SMR. It belongs to the class of dual activeset algorithms. We proved its finite convergence to the optimal solution in, at most, n iterations, where n is the problem size. One of its advantages is that the active set is progressively enlarging by including one or, typically, more constraints per iteration. This resulted in solving large-scale SMR test problems in a few iterations, whereas the size of that problems was prohibitively too large for the conventional quadratic optimization solvers. Although the complexity of the SPAV algorithm is O(n²), its running time was growing in our computational experiments in proportion to n^1:16.

The variance of the error term in ordinary regression models and linear smoothers is usually estimated by adjusting the average squared residual for the trace of the smoothing matrix (the degrees of freedom of the predicted response). However, other types of variance estimators are needed when using monotonic regression (MR) models, which are particularly suitable for estimating response functions with pronounced thresholds. Here, we propose a simple bootstrap estimator to compensate for the over-fitting that occurs when MR models are estimated from empirical data. Furthermore, we show that, in the case of one or two predictors, the performance of this estimator can be enhanced by introducing adjustment factors that take into account the slope of the response function and characteristics of the distribution of the explanatory variables. Extensive simulations show that our estimators perform satisfactorily for a great variety of monotonic functions and error distributions.