Daniel Miller Rotroff

Cleveland Clinic · Department of Quantitative Health Sciences

Background Chemotherapy induced peripheral neuropathy (CIPN) is one of the most common dose-limiting side effects seen among patients with early stage breast cancer and received taxane-containing regimens. The primary clinical manifestation of CIPN is sensory neuropathy such as numbness, tingling and pain in hands and feet, which negatively affect...

Background: Novel deleterious effects of environmental exposures may play a role in the rising incidence of young-onset colorectal cancer (yoCRC). We used metabolomics to assess differences between yoCRC and average-onset CRC (aoCRC), in comparison to healthy controls, which may suggest certain exposure risks. Methods: Patients with stage I-IV CRC...

PurposeNo evidence-based prevention strategies currently exist for cancer-related cognitive decline (CRCD). Although patients are often advised to engage in healthy lifestyle activities (e.g., nutritious diet), little is known about the impact of diet on preventing CRCD. This secondary analysis evaluated the association of pre-treatment diet qualit...

Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is a highly effective treatment option for patients with relapsed/refractory large B cell lymphoma (r/r LBCL). However, widespread use is deterred by development of clinically significant acute inflammatory toxicities, including cytokine release syndrome (CRS) and immune effector cell associa...

Cytomegalovirus (CMV) reactivation from latency following immune dysregulation remains a serious risk for patients, often causing substantial morbidity and mortality. Here, we demonstrate the CMV-encoded G protein-coupled receptor, US28, in coordination with cellular Ephrin receptor A2, attenuates mitogen-activated protein kinase signaling, thereby...

To study neoplasia in tissue culture, cell lines representing the evolution of normal cells to tumor cells are needed. To produce such cells, we developed the AGMK1-9T7 cell line, established cell banks at 10-passage intervals, and characterized their biological properties. Here we examine the evolution of chromosomal DNA copy-number aberrations an...

Introduction: Taxanes are a class of chemotherapeutics commonly used to treat various solid tumors, including breast and ovarian cancers. Taxane-induced peripheral neuropathy (TIPN) occurs in up to 70% of patients, impacting quality of life both during and after treatment. TIPN typically manifests as tingling and numbness in the hands and feet and...

Objective Seizure outcomes after brain surgery for drug-resistant epilepsy (DRE) are very heterogeneous and difficult to predict with models utilizing the current clinical, imaging, and electrophysiological variables. In this pilot study, we investigated whether genetic and molecular biomarkers (e.g., genomic, transcriptomic) can provide additional...

Reports indicate that COVID-19 may impact pancreatic function and increase type 2 diabetes (T2D) risk, although real-world COVID-19 impacts on HbA1c and T2D are unknown. We tested whether COVID-19 increased HbA1c, risk of T2D, or diabetic ketoacidosis (DKA). We compared pre- and post-COVID-19 HbA1c, and T2D risk in a large real-world clinical cohor...

Deep learning (DL) from electronic health records holds promise for disease prediction, but systematic methods for learning from simulated longitudinal clinical measurements have yet to be reported. We compared nine DL frameworks using simulated body mass index (BMI), glucose, and systolic blood pressure trajectories, independently isolated shape a...

The hemoglobin glycation index (HGI) is the difference between observed HbA1c and predicted HbA1c from FPG using linear regression. HGI is an important biomarker of clinical management/drug treatment outcomes and can identify individuals at high risk for multiple adverse events and outcomes before the appearance of clinical symptoms. Here, we sough...

Background & aims: Mixed Lineage Kinase Domain like Pseudokinase (MLKL), a key terminal effector of necroptosis, also plays a role in intracellular vesicle trafficking that is critical for regulating liver inflammation and injury in alcohol-associated liver disease (ALD). While Rip3-/- mice are completely protected from ethanol-induced liver injur...

Potentially severe immune-related adverse events (irAEs) develop in relapsed/refractory large B cell lymphoma (R/R LBCL) patients during treatment with anti-CD19 CAR T-cell therapy. Therefore, prediction and better management of toxicities is critically required to improve patient outcomes. Cytokine release syndrome (CRS), one of the most notable a...

Background Reports indicate that COVID-19 may impact pancreatic function and increase type 2 diabetes (T2D) risk, although real-world COVID-19 impacts on HbA1c and T2D are unknown. We tested whether COVID-19 increased HbA1c, risk of T2D, or diabetic ketoacidosis (DKA). Methods We compared pre- and post-COVID-19 HbA1c, and risk of developing T2D in...

There is mounting evidence that microbes resident in the human intestine contribute to diverse alcohol-associated liver diseases (ALD) including the most deadly form known as alcohol-associated hepatitis (AH). However, mechanisms by which gut microbes synergize with excessive alcohol intake to promote liver injury are poorly understood. Furthermore...

Background Improved detection of hepatocellular carcinoma (HCC) is needed, as current detection methods, such as alpha fetoprotein (AFP) and ultrasound, suffer from poor sensitivity. MicroRNAs (miRNAs) are small, non-coding RNAs that regulate many cellular functions and impact cancer development and progression. Notably, miRNAs are detectable in sa...

BACKGROUND There is mounting evidence that microbes resident in the human intestine contribute to diverse alcohol-associated liver diseases (ALD) including the most deadly form known as alcohol-associated hepatitis (AH). However, mechanisms by which gut microbes synergize with excessive alcohol intake to promote liver injury are poorly understood....

Uncontrolled chemotherapy-induced nausea and vomiting can reduce patients' quality of life and may result in premature discontinuation of chemotherapy. Although nausea and vomiting are commonly grouped together, research has shown that antiemetics are clinically effective against chemotherapy-induced vomiting (CIV) but less so against chemotherapy-...

Aims: Little is known about the impact of weight loss on developing comorbidities in patients with obesity in real-world settings. Understanding health benefits and associated comorbidities with weight loss are critical to addressing the global obesity health epidemic. This study aimed to determine health outcomes associated with weight loss in in...

We sought to identify genome‐wide variants influencing antihypertensive drug response and adverse cardiovascular outcomes, utilizing data from four randomized controlled trials in the International Consortium for Antihypertensive Pharmacogenomics Studies (ICAPS). Genome‐wide antihypertensive drug‐SNP interaction tests for four drug classes (β‐block...

Background Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality worldwide. Improved tools are needed for detecting HCC so that treatment can begin as early as possible. Current diagnostic approaches and existing biomarkers, such as alpha-fetoprotein (AFP) lack sensitivity, resulting in too many false negative diagnoses. Machine lea...

Background: Acute and chronic alcohol abuse has adverse impacts on both the innate and adaptive immune response, which may result in reduced resistance to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and promote the progression of coronavirus disease 2019 (COVID-19). However, there are no large population-based data evalu...

Objective: Current type 2 diabetes (T2D) management contraindicates intensive glycemia treatment in patients with high cardiovascular disease (CVD) risk and is partially motivated by evidence of harms in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Heterogeneity in response to intensive glycemia treatment has been observed...

Objective: To identify single nucleotide polymorphisms (SNPs) associated with post-operative seizure freedom in temporal lobe epilepsy (TLE) patients. Background: Surgical resection is the treatment of choice for up to 80% of pharmaco-resistant TLE; however, heterogeneity in response demands improvements in the prediction of postoperative seizure...

Background Acute and chronic alcohol abuse have adverse impacts on both the innate and adaptive immune response, which may result in reduced resistance to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and promote the progression of coronavirus disease 2019 (COVID-19). However, there are no large population-based data evalua...

Immune checkpoint inhibitors (ICIs) blocking programmed death receptor 1 or its ligand (anti-PD-1/PD-L1) are a burgeoning class of promising cancer treatments. However, not all patients respond to these treatments. Although studies have suggested potential biomarkers to predict patients likely to respond to treatment, no consensus biomarker has bee...

Background: CAR T-cells that target CD19 have been approved by the FDA for treatment of relapsed/refractory large B cell lymphoma (r/r LBCL). Despite clinical efficacy in chemo-refractory patients, the benefit of this approach is often complicated by potentially severe toxicities such as cytokine release syndrome (CRS) and immune effector cell-asso...

Abstract (word counts: 259) Background & Aims We aimed to examine the association between regular use of acid suppressants and risk of SARS-CoV-2 infection and death in patients with corona virus infectious disease 2019 (COVID-19). Methods We conducted a retrospective cohort study using data from the UK biobank. Totally 9469 participants aged 50-8...

Reductions in genotyping costs and improvements in computational power have made conducting genome-wide association studies (GWAS) standard practice for many complex diseases. GWAS is the assessment of genetic variants across the genome of many individuals to determine which, if any, genetic variants are associated with a specific trait. As with an...

Background & aims: Given the lack of effective therapies and high mortality in acute alcohol-associated hepatitis (AH), it is important to develop rationally-designed biomarkers for effective disease management. Complement, a critical component of the innate immune system, contributes to uncontrolled inflammatory responses leading to liver injury,...

Breath analysis is the study of volatile organic compounds (VOC's) in exhaled breath. This analysis provides information on the body's condition. In this study we investigated the relationship between 22 VOC's detected in exhaled breath and plasma headspace using a selected ion flow tube mass spectrometer (SYFT-MS). We compared pairs of exhaled bre...

Bariatric surgery improves glycemic control better than medical therapy; however, the effect of bariatric surgery on HDL function is not well characterized. Serum samples were available at baseline, 1-, and 5-years post procedures, for 90 patients with obesity and type 2 diabetes who were randomized to intensive medical therapy (n = 20), Roux-en-Y...

Hepatocellular carcinoma (HCC) and secondary liver tumors, such as colorectal cancer liver metastases are significant contributors to the overall burden of cancer‐related morality. Current biomarkers, such as alpha‐fetoprotein (AFP) for HCC, result in too many false negatives, necessitating noninvasive approaches with improved sensitivity. Volatile...

The cardiovascular benefits of fibrates have been shown to be heterogeneous and to depend on the presence of atherogenic dyslipidemia. We investigated whether genetic variability in the PPARA gene, coding for the pharmacological target of fibrates (PPAR-alpha), could be used to improve the selection of patients with type 2 diabetes who may derive c...

Background and aims: Sarcopenia or skeletal muscle loss adversely affects outcomes in cirrhosis. The impact of etiology of liver disease on the severity or the rate of muscle loss is not known. Methods: Consecutive, well-characterized adult patients with cirrhosis due to viral hepatitis (VH), alcoholic liver disease (ALD), or nonalcoholic fatty...

Alzheimer’s disease (AD) is the most common cause of dementia. The mechanism of disease development and progression is not well understood, but increasing evidence suggests multifactorial etiology, with a number of genetic, environmental, and aging-related factors. There is a growing body of evidence that metabolic defects may contribute to this co...

Developing predictive and transparent approaches to the analysis of metabolite profiles across patient cohorts is of critical importance for understanding the events that trigger or modulate traits of interest (e.g., disease progression, drug metabolism, chemical risk assessment). However, metabolites’ chemical structures are still rarely used in t...

Hepatic venous pressure gradient (HVPG) is known to correlate with severity of portal hypertension in patients with liver cirrhosis. This retrospective study investigated the clinical value of preoperative measurement of HVPG in patients who underwent adult‐to‐adult LDLT and its predictive value for hepatic hemodynamics after graft reperfusion. For...

Rare variants are of increasing interest to genetic association studies because of their etiological contributions to human complex diseases. Due to the rarity of the mutant events, rare variants are routinely analyzed on an aggregate level. While aggregation analyses improve the detection of global-level signal, they are not able to pinpoint causa...

Quantile-quantile plots of p-values for PLA2G7 simulation study under the null hypothesis of no causal variants using different methods. SVT: single variant test; POINT-Burden: POINT test using local burden kernel; POINT-Linear: POINT test using local linear kernel; SCAN: scan statistic method (from the p-values of the best window); ADA of Lin (201...

Empirical receiver operating characteristic (ROC) curves for continuous outcomes with n = 1000 subjects under different scenarios of causal variants. The simulation scenarios are listed in Table 2. The Y-axis is the true positive rate (i.e., sensitivity) and the X-axis is the false positive rate (i.e., 1-specificity). Red dotted line: single varian...

Selection performance of binary-trait simulations with n = 1000 subjects. Selection performance for single variant test (SVT), scan statistic (SCAN), ADA, REBET, POINT test using local burden kernel (POINT-Burden), and POINT test using local linear kernel (POINT-Linear). The best performed methods (based on the composite F-measure) are shown in bol...

ANGPTL4 rare variant summary information, locations on the protein tertiary structure, and results of association tests with high-density lipoproteins (HDL). (PDF)

Empirical receiver operating characteristic (ROC) curves for binary outcomes with n = 2000 subjects under different scenarios of causal variants. The simulation scenarios are listed in Table 3. The Y-axis is the true positive rate (i.e., sensitivity) and the X-axis is the false positive rate (i.e., 1-specificity). Red dotted line: single variant te...

Selection performance of continuous-trait simulations with n = 1000 subjects. Selection performance for single variant test (SVT), REBET, POINT test using local burden kernel (POINT-Burden), and POINT test using local linear kernel (POINT-Linear). The best performed methods (based on the composite F-measure) are shown in bold. (PDF)

Information-borrowing map for each variant in PLA2G7. Information-borrowing map shows the amount of borrowing from neighboring variants for each of the PLA2G7 variants for different values of c, with darker color representing higher levels of contribution via the variant correlation matrix R. (PDF)

Empirical receiver operating characteristic (ROC) curves for binary outcomes with n = 1000 subjects under different scenarios of causal variants. The simulation scenarios are listed in Table 3. The Y-axis is the true positive rate (i.e., sensitivity) and the X-axis is the false positive rate (i.e., 1-specificity). Red dotted line: single variant te...

PLA2G7 rare variant summary information. Minor allele frequency and protein coordinate information for the rare variants in PLA2G7. The 3D coordinates are obtained from PDB entry 3F96. (PDF)

PCSK9 rare variant summary information. Minor allele frequency and protein coordinate information for the rare variants in PCSK9. The 3D coordinates are obtained from PDB entry 4K8R. (PDF)

Resampling approach to obtain the p-value of the localized test for variant m. (PDF)

Empirical receiver operating characteristic (ROC) curves for continuous outcomes with n = 2000 subjects under different scenarios of causal variants. The simulation scenarios are listed in Table 2. The Y-axis is the true positive rate (i.e., sensitivity) and the X-axis is the false positive rate (i.e., 1-specificity). Red dotted line: single varian...

PCSK9 information-borrowing map. Information-borrowing map shows the amount of borrowing from neighboring variants for the chosen best c value for the local kernel test of association between the rare variants in PCSK9 and LDL. (TIFF)

CETP rare variant summary information, locations on the protein tertiary structure, and results of association tests with high-density lipoproteins (HDL). (PDF)

Introduction: Increasing evidence suggests a role for the gut microbiome in central nervous system disorders and a specific role for the gut-brain axis in neurodegeneration. Bile acids (BAs), products of cholesterol metabolism and clearance, are produced in the liver and are further metabolized by gut bacteria. They have major regulatory and signa...

Objective: We evaluated whether the increasing number of genetic loci for coronary artery disease (CAD) identified in the general population could be used to predict the risk of major CAD events (MCE) among participants with type 2 diabetes at high cardiovascular risk. Research design and methods: A weighted genetic risk score (GRS) derived from...

Background Gene set analysis is a valuable tool to summarize high-dimensional gene expression data in terms of biologically relevant sets. This is an active area of research and numerous gene set analysis methods have been developed. Despite this popularity, systematic comparative studies have been limited in scope. Methods In this study we presen...

Rare variants are of increasing interest to genetic association studies because of their etiological contributions to human complex diseases. Due to the rarity of the mutant events, rare variants are routinely analyzed on an aggregate level. While aggregation analyses improve the detection of global-level signal, they are not able to pinpoint causa...

Metformin is the first line treatment for type 2 diabetes (T2D). Although widely prescribed, the glucose-lowering mechanism for metformin is incompletely understood. Here we used a genome-wide association approach in a diverse group of individuals with T2D from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) clinical trial to identif...

Introduction Increasing evidence suggests a role for the gut microbiome in central nervous system disorders and specific role for the gut-brain axis in neurodegeneration. Bile acids (BA), products of cholesterol metabolism and clearance, are produced in the liver and are further metabolized by gut bacteria. They have major regulatory and signaling...

Background: Although hydrochlorothiazide (HCTZ) is a well-established first-line antihypertensive in the United States, <50% of HCTZ treated patients achieve blood pressure (BP) control. Thus, identifying biomarkers that could predict the BP response to HCTZ is critically important. In this study, we utilized metabolomics, genomics, and lipidomics...

Background Gastric cancer (GC) is a major cause of cancer deaths, especially in Eastern Asia. Current classification systems, including the WHO, Lauren, and TCGA, have clarified the pathological and molecular profiles of GC. However, these classifications lack an association with clinical outcome and guidance for medication selection. Objective We...

Data S1. Supplemental methods. Table S1. Thirteen Metabolites Significantly Associated With Hydrochlorothiazide Blood Pressure Response of Whites in the PEAR HCTZ Monotherapy Study Table S2. Genes in the Sphingolipid Metabolism Canonical Pathway Table S3. Characteristics of White PEAR Participants Included in the Lipidomics Analyses Table S4. T...

Multi-targeted tyrosine kinase inhibitors (TKIs) have broad efficacy and similar FDA-approved indications, suggesting shared molecular drug targets across cancer types. Irrespective of tumor type, 20-30% of patients treated with multi-targeted TKIs demonstrate intrinsic resistance, with progressive disease as a best response. We conducted a retrosp...

Alzheimer’s disease (AD) is the most common neurodegenerative disease presenting major health and economic challenges that continue to grow. Mechanisms of disease are poorly understood but significant data point to metabolic defects that might contribute to disease pathogenesis. The Alzheimer Disease Metabolomics Consortium (ADMC) in partnership wi...