Manuela Zucknick

University of Oslo · Department of Biostatistics

In this paper we propose PIICM, a probabilistic framework for dose–response prediction in high-throughput drug combination datasets. PIICM utilizes a permutation invariant version of the intrinsic co-regionalization model for multi-output Gaussian process regression, to predict dose–response surfaces in untested drug combination experiments. Couple...

Aim: To describe hand use development in children with unilateral cerebral palsy who did/did not participate in constraint-induced movement therapy (CIMT) before 7 years of age. Method: The study included 334 participants (18 months-12 years) who were assessed with 1,565 Assisting Hand Assessments (AHAs) and categorized into no intensive trainin...

In this paper, we consider the regularized multi-response regression problem where there exists some structural relation within the responses and also between the covariates and a set of modifying variables. To handle this problem, we propose MADMMplasso, a novel regularized regression method. This method is able to find covariates and their corres...

Given that both hearing and touch are ‘mechanical senses’ that respond to physical pressure or mechanical energy and that individuals appear to have a characteristic internal or spontaneous tempo, individual preferences in musical and touch rhythms might be related. We explored this in two experiments probing individual preferences for tempo in the...

Identification of genomic, molecular and clinical markers predictive of patient survival is important for developing personalized disease prevention, diagnostic and treatment approaches. Modern omics technologies have made it possible to investigate the prognostic impact of markers at multiple molecular levels, including genotype, DNA methylation,...

Motivation There is a rapidly growing interest in high-throughput drug combination screening to identify synergizing drug interactions for treatment of various maladies, such as cancer and infectious disease. This creates the need for pipelines that can be used to design such screens, perform quality control on the data, and generate data files tha...

The analysis of whole genomes of pan‐cancer data sets provides a challenge for researchers, and we contribute to the literature concerning the identification of robust subgroups with clear biological interpretation. Specifically, we tackle this unsupervised problem via a novel rank‐based Bayesian clustering method. The advantages of our method are:...

Methotrexate is one of the cornerstones of rheumatoid arthritis (RA) therapy. Genetic factors or single nucleotide polymorphisms (SNPs) are responsible for 15%–30% of the variation in drug response. Identification of clinically effective SNP biomarkers for predicting methotrexate (MTX) sensitivity has been a challenge. The aim of this study was to...

Enrichment analysis has been widely used to study whether predefined sets of genes or other molecular features are over-represented in a ranked list associated with a disease or other phenotype. However, computational tools that perform enrichment analysis and visualization are usually limited to predefined sets available from public databases. To...

There is a rapidly growing interest in high-throughput drug combination screening to identify synergizing drug interactions for treatment of various maladies, such as cancer and infectious disease. This creates the need for pipelines that can be used to design such screens, perform quality control on the data, and generate data files that can be an...

Abstract Background Placenta-derived proteins in the systemic maternal circulation are suggested as potential biomarkers for placental function. However, the identity and longitudinal patterns of such proteins are largely unknown due to the inaccessibility of the human placenta and limitations in assay technologies. We aimed to identify proteins de...

Purpose Placental weight (PW) has been found to mediate the main effect of maternal BMI on fetal size. Still, the BMI–PW association is poorly understood. Therefore, we aimed to explore potential explanatory variables, including gestational weight gain (GWG), early- and late-pregnancy circulating levels of maternal glucose, insulin, leptin, adipone...

Current statistical models for drug response prediction and biomarker identification fall short in leveraging the shared and unique information from various cancer tissues and multi-omics profiles. We developed mix-lasso model that introduces an additional sample group penalty term to capture tissue-specific effects of features on pan-cancer respon...

Background Foot disorders affect up to one quarter of the adult population. Plantar fasciopathy is a common cause of foot pain associated with decreased activity level and quality of life. Patient-reported outcome measures are important in assessing the burden of a condition as well as in research on the effects of interventions. The Foot Function...

In this paper we propose PIICM, a probabilistic framework for dose-response prediction in high-throughput drug combination datasets. PIICM utilizes a Permutation Invariant version of the Intrinsic Co-regionalization Model for multi-output Gaussian Process regression, to predict dose-response surfaces in untested drug combination experiments. Couple...

In this paper we propose PIICM, a probabilistic framework for dose-response prediction in high-throughput drug combination datasets. PIICM utilizes a P ermutation- I nvariant version of the I ntrinsic C o-regionalization M odel for multi-output Gaussian Process regression, to predict dose-response surfaces in untested drug combination experiments....

Background Important objectives in cancer research are the prediction of a patient’s risk based on molecular measurements such as gene expression data and the identification of new prognostic biomarkers (e.g. genes). In clinical practice, this is often challenging because patient cohorts are typically small and can be heterogeneous. In classical su...

In molecular biology, advances in high-throughput technologies have made it possible to study complex multivariate phenotypes and their simultaneous associations with high-dimensional genomic and other omics data, a problem that can be studied with high-dimensional multi-response regression, where the response variables are potentially highly corre...

The effect of cancer therapies is often tested pre-clinically via in vitro experiments, where the post-treatment viability of the cancer cell population is measured through assays estimating the number of viable cells. In this way, large libraries of compounds can be tested, comparing the efficacy of each treatment. Drug interaction studies focus o...

Background Chronic brain pathology and pre-stroke cognitive impairment (PCI) is predictive of post-stroke dementia. The aim of the current study was to measure pre-stroke neurodegenerative and vascular disease burden found on brain MRI and to assess the association between pre-stroke imaging pathology and PCI, whilst also looking for potential sex...

Aim To describe the development of hand use during bimanual activities among children with unilateral cerebral palsy (CP). Method A cohort of 166 children (79 females, 87 males; age range 18mo–13y, mean [SD] age at first assessment 37.6mo [20.5mo]) with unilateral CP, registered in the Norwegian CP Follow-up Program with two or more Assisting Hand...

In molecular biology, advances in high-throughput technologies have made it possible to study complex multivariate phenotypes and their simultaneous associations with high-dimensional genomic and other omics data, a problem that can be studied with high-dimensional multi-response regression, where the response variables are potentially highly corre...

Rheumatoid arthritis (RA) is a complex disease with a wide range of underlying susceptibility factors. Recently, dysregulation of microRNAs (miRNAs) in RA have been reported in several immune cell types from blood. However, B cells have not been studied in detail yet. Given the autoimmune nature of RA with the presence of autoantibodies, CD19+ B ce...

The effect of cancer therapies is often tested pre-clinically via in-vitro experiments, where the post-treatment viability of the cancer cell population is measured through assays estimating the number of viable cells. In this way, large libraries of compounds can be tested, comparing the efficacy of each treatment. Drug interaction studies focus o...

Context Lifestyle interventions have not efficaciously reduced complications caused by maternal weight on fetal growth, requiring insight into explanatory mediators. Objective We hypothesized that maternal mediators, including adiponectin, leptin, insulin, and glucose, mediate effects of pregestational BMI (pBMI) and gestational weight gain (GWG)...

It is becoming increasingly common to study the complex association between multiple outcomes and high-dimensional predictors in biomedicine. However, the related multiple outcomes and related high-dimensional predictors require flexible and efficient joint statistical models. We propose a multivariate structured Bayesian variable selection model t...

The molecular characterization of tumor samples by multiple omics data sets of different types or modalities (e.g. gene expression, mutation, CpG methylation) has become an invaluable source of information for assessing the expected performance of individual drugs and their combinations. Merging relevant information from the omics data modalities p...

Ciliopathies are clinically and genetically heterogeneous diseases. We studied three patients from two independent families presenting with features of Joubert syndrome: abnormal breathing pattern during infancy, developmental delay/in-tellectual disability, cerebellar ataxia, molar tooth sign on magnetic resonance imaging scans, and polydactyly. W...

Objective: The role of neutrophil extracellular traps (NETs) in acute heart failure is unknown. We recently showed that interleukin 8, a putative NETs stimulator, was associated with myocardial recovery in acute heart failure complicating ST-elevation myocardial infarction (STEMI). In this exploratory post-hoc study, we aimed to investigate the ro...

Background More accurate risk assessments are needed to improve prostate cancer management. Objective To identify blood-based protein biomarkers that provided prognostic information for risk stratification. Design, setting, and participants Mass spectrometry was used to identify biomarker candidates from blood, and validation studies were perform...

Introduction: To better understand the development of post-stroke cognitive impairment, we explored the association between pre-stroke neuroimaging features and pre-stroke cognitive impairment and investigated possible gender differences. Few previous studies on this topic have been performed. Methods: In this large prospective longitudinal multice...

Objective To evaluate the effect of a dialogue-based intervention targeting psychosocial well-being at 12 months post-stroke. Design Multicenter, prospective, randomized, assessor-blinded, controlled trial with two parallel groups. Setting Community. Subjects Three-hundred and twenty-two adults (⩾18 years) with stroke within the last four weeks...

Background Vancomycin trough levels are frequently subtherapeutic in intensive care unit (ICU) patients. The aim of this study was to identify patients at risk of therapeutic failure defined as vancomycin area‐under‐the‐curve0‐24/minimum inhibitory concentration (AUC0‐24/MIC) <400, and to examine possible effects of different MICs, the variability...

High-throughput sequencing has emerged as the favoured method to study microRNA (miRNA) expression, but biases introduced during library preparation have been reported. We recently compared the performance (sensitivity, reliability, titration response and differential expression) of six commercially-available kits on synthetic miRNAs and human RNA,...

Important objectives in cancer research are the prediction of a patient's risk based on molecular measurements such as gene expression data and the identification of new prognostic biomarkers (e.g. genes). In clinical practice, this is often challenging because patient cohorts are typically small and can be heterogeneous. In classical subgroup anal...

Current studies addressing the influence of interleukin-33 or its receptor (IL-33R/ST2) on development of atopic dermatitis-like inflammation in mice have reported conflicting results. We compared the response in single- and double-deficient IL-33−/−/ST2−/− C57BL/6J BomTac mice in the well-established calcipotriol-induced model of atopic dermatitis...

Background Keratoacanthoma (KA) has a unique life cycle of rapid growth and spontaneous regression that shows similarities to the hair follicle cycle, which involves an active Wnt signaling during physiological regeneration. We analyzed the expression of the Wnt signaling proteins β‐catenin, Lef1, Sox9, and Cyclin D1 in young and old human KAs to i...

High-throughput sequencing has emerged as the favoured method to study microRNA (miRNA) expression, but biases introduced during library preparation have been reported. To assist researchers choose the most appropriate library preparation kit, we recently compared the performance of six commercially-available kits on synthetic miRNAs and human RNA,...

Large‐scale in vitro drug sensitivity screens are an important tool in personalized oncology to predict the effectiveness of potential cancer drugs. The prediction of the sensitivity of cancer cell lines to a panel of drugs is a multivariate regression problem with high dimensional heterogeneous multiomics data as input data and with potentially st...

DNA methylation data-based precision cancer diagnostics is emerging as the state of the art for molecular tumor classification. Standards for choosing statistical methods with regard to well-calibrated probability estimates for these typically highly multiclass classification tasks are still lacking. To support this choice, we evaluated well-establ...

High-throughput sequencing is increasingly favoured to assay the presence and abundance of microRNAs (miRNAs) in biological samples, even from low RNA amounts, and a number of commercial vendors now offer kits that allow miRNA sequencing from sub-nanogram (ng) inputs. Although biases introduced during library preparation have been documented, the r...

Objective: To evaluate the effect of a dialogue-based intervention on psychosocial well-being 6 months after stroke. Design: Multicentre, prospective, randomized con- trolled trial. Subjects: Adults (aged ≥18 years) who had their first or recurrent stroke within the last month, were medically stable, had sufficient cognitive functioning to particip...

High-throughput sequencing is increasingly favoured to assay the presence and abundance of micro RNAs (miRNAs) in biological samples, even from low RNA amounts, and a number of commercial vendors now offer kits that allow miRNA sequencing from sub-nanogram (ng) inputs. However, although biases introduced during library preparation have been documen...

Chronic lymphocytic leukemia (CLL) is known for its strong dependency on the tumor microenvironment. We found progranulin (GRN), a protein that has been linked to inflammation and cancer, to be upregulated in the serum of CLL patients compared to healthy controls, and increased GRN levels to be associated with an increased hazard for disease progre...

The molecular characterization of tumor samples by multiple omics data sets of different types or modalities (e.g. gene expression, mutation, CpG methylation) has become an invaluable source of information for assessing the expected performance of individual drugs and their combinations. Merging the relevant information from the omics data modaliti...

Increasing effort is devoted to the study of the combined effect of two drugs when they are administered simultaneously to the same cell culture. In this paper, we introduce a new approach to estimate which part of the effect of the two drugs is due to the interaction of the compounds, i.e. which is due to synergistic or antagonistic effects of the...

Background Several studies have documented the variety of post-stroke psychosocial challenges, which are complex, multifaceted, and affect a patient’s rehabilitation and recovery. Due to the consequences of these challenges, psychosocial well-being should be considered an important outcome of the stroke rehabilitation. Thus, a valid and reliable in...

Aim To evaluate the effect of a dialogue-based intervention to promote psychosocial well-being at 12 months post-stroke. Methods Trial design Multicenter prospective RCT with two parallel groups. Participants were assessed at 1-, 6-, and 12-months post-stroke. Participants  Adults (aged ≥18), stroke within the last month, medically stable, suffici...

Targeted cancer drugs have been developed to interfere with specific molecular targets, which are expected to affect the growth of cancer cells in a way that can be characterized by multi-omics data. The prediction of cancer drug sensitivity simultaneously for multiple drugs based on heterogeneous multi-omics data (e.g., mRNA expression, DNA copy n...

Purpose Precise radiological assessment of tumour volume is important in the follow-up of non-functioning pituitary adenomas (NFPAs). We compared the reliability of two methods for tumour volume measurements in the pre- and postoperative setting. Methods We assessed the volume of 22 NFPAs at magnetic resonance imaging (MRI) scans before surgery an...

Introduction Middle cerebral artery (MCA) and umbilical artery (UA) Doppler blood flow pulsatility indices (PIs) and MCA peak systolic velocity (PSV) are essential variables for clinically evaluating fetal well-being. Here we examined how a maternal meal influenced these Doppler blood flow velocity variables. Methods This prospective cohort study...

Cancers elicit an immune response by modifying the microenvironment. The immune system plays a pivotal role in cancer recognition and eradication. While the potential clinical value of infiltrating lymphocytes at the tumor site has been assessed in breast cancer, circulating cytokines – the molecules coordinating and fine-tuning immune response – a...

Purpose: Gonadotroph tumours are the most abundant of the clinically silent pituitary tumours. There is a lack of reliable prognostic markers predicting their clinical course. Our aim was to determine the level of E-cadherin and N-cadherin in a cohort of clinically silent gonadotroph pituitary tumours, and compare them to the rate of reinterventio...

Background: Chronic Fatigue Syndrome (CFS) is one of the most important causes of disability among adolescents while limited knowledge exists on genetic determinants underlying disease pathophysiology. Methods: We analyzed deregulated immune-gene modules using Pathifier software on whole blood gene expression data (29 CFS patients, 18 controls)....

Background A Bayesian mixed model approach using integrated nested Laplace approximations (INLA) allows us to construct flexible models that can account for pedigree structure. Using these models, we estimate genome-wide patterns of DNA methylation heritability (h²), which are currently not well understood, as well as h² of blood lipid measurements...

Background: An important feature in many genomic studies is quality control and normalization. This is particularly important when analyzing epigenetic data, where the process of obtaining measurements can be bias prone. The GAW20 data was from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN), a study with multigeneration families, wh...