Quantitative proteomics identifies and validates urinary biomarkers of rhabdomyosarcoma in children.

BACKGROUND: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma with poor prognosis in children. The 5-year survival rate for early RMS has improved, whereas it remains unsatisfactory for advanced patients. Urine can rapidly reflect changes in the body and identify low-abundance proteins. Early screening of tumor markers through urine in RMS allows for earlier treatment, which is associated with better outcomes. METHODS: RMS patients under 18 years old, including those newly diagnosed and after surgery, were enrolled. Urine samples were collected at the time points of admission and after four cycles of chemotherapy during follow-up. Then, a two-stage workflow was established. (1) In the discovery stage, differential proteins (DPs) were initially identified in 43 RMS patients and 12 healthy controls (HCs) using a data-independent acquisition method. (2) In the verification stage, DPs were further verified as biomarkers in 54 RMS patients and 25 HCs using parallel reaction monitoring analysis. Furthermore, a receiver operating characteristic (ROC) curve was used to construct the protein panels for the diagnosis of RMS. Gene Ontology (GO) and Ingenuity Pathway Analysis (IPA) software were used to perform bioinformatics analysis. RESULTS: A total of 251 proteins were significantly altered in the discovery stage, most of which were enriched in the head, neck and urogenital tract, consistent with the most common sites of RMS. The most overrepresented biological processes from GO analysis included immunity, inflammation, tumor invasion and neuronal damage. Pathways engaging the identified proteins revealed 33 common pathways, including WNT/ß-catenin signaling and PI3K/AKT signaling. Finally, 39 proteins were confirmed as urinary biomarkers for RMS, and a diagnostic panel composed of 5 candidate proteins (EPS8L2, SPARC, HLA-DRB1, ACAN, and CILP) was constructed for the early screening of RMS (AUC: 0.79, 95%CI = 0.66 ~ 0.92). CONCLUSIONS: These findings provide novel biomarkers in urine that are easy to translate into clinical diagnosis of RMS and illustrate the value of global and targeted urine proteomics to identify and qualify candidate biomarkers for noninvasive molecular diagnosis.

Accuracy of equations for predicting 24-h urinary potassium excretion from spot urine samples in Chinese children.

Accurate assessments of potassium intake in children are important for the early prevention of CVD. Currently, there is no simple approach for accurate estimation of potassium intake in children. We aim to evaluate the accuracy of 24-h urinary potassium excretion (24UKV) estimation in children using three common equations: the Kawasaki, Tanaka and Mage formulas, in a hospital-based setting. A total of 151 participants aged 5-18 years were initially enrolled, and spot urine samples were collected in the whole 24-h duration to measure the concentrations of potassium and creatinine. We calculated the mean difference, absolute and relative difference and misclassification rate between measured 24UKV and the predicted ones using Kawasaki, Tanaka and Mage formulas in 129 participants. The mean measured 24UKV was 1193·3 mg/d in our study. Mean differences between estimated and measured 24UKV were 1215·6, -14·9 and 230·3 mg/d by the Kawasaki, Tanaka and Mage formulas, respectively. All estimated 24UKV were significantly different from the measured values in all the time point (all P < 0·05), except for the predicted values from Tanaka formula using morning, afternoon and evening spot urine. The proportions with relative differences over 40 % were 87·2%, 32·5% and 47·3 % for Kawasaki, Tanaka and Mage formulas, respectively. Misclassification rates were 91·5 % for Kawasaki, 44·4 % for Tanaka and 58·9 % for Mage formula at the individual level. Our findings showed that misclassification could occur on the individual level when using Kawasaki, Tanaka and Mage formulas to estimate 24UKV from spot urine in the child population.

Cost-effectiveness analysis of dasatinib versus imatinib in pediatric philadelphia chromosome-positive acute lymphoblastic leukemia patients in China.

BACKGROUND: Dasatinib and imatinib are the recommended tyrosine kinase inhibitors (TKIs) for treating pediatric Philadelphia-positive acute lymphoblastic leukemia (Ph + ALL), and the one which has been approved indication in China is imatinib. Recently, clinical demand for Ph + ALL treatment is becoming unmet gradually with the increasing resistance of imatinib. There are some studies reporting the better efficacy and comparative safety of dasatinib compared with imatinib, but no economic comparison has been published. This study aims to supplement economic evidence by comparing the cost-effectiveness between imatinib and dasatinib in treating pediatric patients with Ph+ ALL in China, and to help clinical rational drug use via multi-dimensional value assessment. METHODS: A decision tree model combined with a 10-year Markov model were established based on the disease progression. The parameters were collected from published literatures and our hospital's electronic medical records. From the health system perspective, the incremental cost-effectiveness ratio (ICER) between the two treatment groups was calculated through cost-effectiveness analysis and then compared with the willingness-to-pay (WTP) threshold. The set WTP threshold in this study was 1 times per capita gross domestic product (GDP) of China, as recommended by the World Health Organization. Direct medical costs and quality-adjusted life years (QALYs) were calculated and discounted at 5%. The sensitivity analyses were conducted to assess the uncertainty and robustness of the results. RESULTS: The total costs were CNY 1,020,995.35 and CNY 1,035,788.50 in imatinib group and dasatinib group during the 10-year simulation, and the total QALYs were 2.59 and 4.84. Compared with the imatinib treatment group, the ICER was around CNY 6,575.78/ QALY, which was less than the set threshold CNY 70,892/ QALY. The sensitive analyses indicated the robustness of the results. CONCLUSIONS: The cost-effectiveness analysis shows the potential cost-effective advantages of adding dasatinib comparing with adding imatinib for pediatric Ph + ALL patients in China under the set WTP threshold, which indicates that those patients could achieve more QALYs by paying acceptable fee.

Effect of Community-Based Social Skills Training and Tai-Chi Exercise on Outcomes in Patients with Chronic Schizophrenia: A Randomized, One-Year Study.

BACKGROUND: Antipsychotic drugs are limited in their ability to improve negative symptoms, quality of life, and medication adherence in patients with schizophrenia. The addition of nonpharmacological interventions like social skills training has a positive effect on medication adherence and decreases rehospitalization rates but is limited in improving patients' symptoms, aggressive behaviors, and quality of life. Aerobic exercise, especially Tai-chi, can potentially reduce psychopathological and negative symptoms, decrease aggressive behaviors, and improve quality of life. It is an ideal rehabilitation intervention for patients with schizophrenia. However, no study has investigated the effects of social skills training plus Tai-chi on outcomes among outpatients with schizophrenia. This study analyzes the effect of antipsychotics combined with community-based integrated interventions on outcomes of schizophrenia. METHODS: In this study, a 24-session social skills training plus Tai-chi was used in community settings among patients with schizophrenia. A total of 244 patients were randomly assigned to medication treatment alone (MTA group) or community-based integrated intervention (CBII group), which accepted social skills training plus Tai-chi in addition to medication treatment. Generalized linear mixed models were used to evaluate the intervention effect (group effect), intervention effect over time (time effect), and interaction effect (group × time effect). t tests were used to evaluate between-group differences on clinical variables. Multiple linear regression analysis was used to analyze the differences between the intervention at 12 months and baseline for the Positive and Negative Syndrome Scale (PANSS) negative symptoms and quality of life-social domain. RESULTS: Compared with the MTA group, the CBII group had lower scores on PANSS (F = 17.312, p < 0.001) and negative symptoms (F = 44.909, p < 0.001), a lower risk for aggressive behavior (F = 12.382, p < 0.001), and a greater improvement in adherence to medication (F = 12.391, p < 0.001) after 1 year of intervention. The changes in PANSS total scores, negative scores, and social domain of the World Health Organization Quality of Life Scale-Brief version (WHOQOL-BREF) from baseline to 12 months were significant between the two groups (PANSS total score: t = 4.839, p < 0.001; negative symptoms: t = 8.250, p < 0.001, and quality of life-social domain: t = -2.171, p = 0.031). Multiple linear regression analysis also showed that the intervention was significantly effective for changes from baseline to 12 months on PANSS total score (B = 0.804, p < 0.001), negative score (B = 0.709, p < 0.001), and social domain of quality of life (B = -0.673, p = 0.044). CONCLUSIONS: This study suggested that the community-based integrated intervention such as social skills training plus Tai-chi should be part of a rehabilitation effort for patients with schizophrenia in order to improve clinical symptoms, quality of life, and medication adherence.

Association of KCNB1 polymorphisms with lipid metabolisms and insulin resistance: a case-control design of population-based cross-sectional study in Chinese Han population.

BACKGROUND: In our previous study, we had assessed in the Chinese Han population the association of KCNB1 rs1051295 with metabolic traits indicating metabolic syndrome, and showed that KCNB1 rs1051295 genotype TT was associated with increase of waist to hip ratio (WHR), fasting insulin (FINS), triglycerides (TG) and decreased insulin sensitivity at basal condition. Here, we aimed at detecting whether there were associations between other tag SNPs of KCNB1 and favorable or unfavorable metabolic traits. METHODS: We conducted a case-control design of population-based cross-sectional study to investigate the association between each of the 22 candidates tag SNPs of KCNB1 and metabolic traits in a population of 733 Chinese Han individuals. The association was assessed by multiple linear regression analysis or unconditional logistic regression analysis. RESULTS: We found that among the 22 selected tag SNPs, four were associated with an increase (rs3331, rs16994565) or decrease (rs237460, rs802950) in serum cholesterol levels; two of these (rs237460, rs802590) further associated or were associated with reduced serum LDL-cholesterol. Two novel tag SNPs (rs926672, rs1051295) were associated with increased serum TG levels. We also showed that KCNB1 rs926672 associated with insulin resistance by a case-control study, and two tag SNPs (rs2057077and rs4810952) of KCNB1 were associated with the measure of insulin resistance (HOMA-IR) in a cross-section study. CONCLUSION: These results indicate that KCNB1 is likely associated with metabolic traits that may either predispose or protect from progression to metabolic syndrome. This study provides initial evidence that the gene variants of KCNB1, encoding Kv2.1 channel, is associated with perturbation of lipid metabolism and insulin resistance in Chinese Han population.

Budesonide/formoterol maintenance and reliever therapy in childhood asthma: Real-world effectiveness and economic assessment.

INTRODUCTION: The study aims to compare the real-world effectiveness and economy of the budesonide/formoterol reliever and maintenance therapy (SMART) with fixed-dose inhaled corticosteroids (ICS)/long-acting b-agonist (LABA) or ICS alone plus as-needed, short-acting ß2 agonists (SABA) in pediatric patients. METHODS: The outpatient data warehouse of a hospital in China was used. A total of 103 patients under 18 years old in the SMART group and 63 patients in the control group were included from January 1, 2020 to December 31, 2021. The effectiveness was assessed using asthma attacks and lung function at baseline, 6 months and 12 months follow-up. Cost-effectiveness analysis was performed with a three-state Markov model from the healthcare system perspective. One-way sensitivity analyses and probabilistic sensitivity analyses were performed to check the robustness of the results. RESULTS: The SMART regimen was more effective than other strategies in reducing the risk of mild and severe attacks in the real-life management of childhood asthma. Patients in both groups showed significant improvement in lung function at 6 and 12 months in contrast to baseline. Compared with other strategies, the forced expiratory volume in 1 s (FEV1 ) level in the SMART group was markedly improved at 6 months. The total cost of outpatient service using the SMART regimen was lower than that of other strategies, while the drug costs were similar in different groups. Incremental cost-effectiveness analysis results showed that using the SMART regimen reduced the total cost by approximately CNY 10,516.11 per year with a 0.12 quality-adjusted life year (QALYs) increase. Sensitive analyses supported that the SMART regimen was the dominant choice at the willingness-to-pay threshold of CNY 85,698, per capita GDP in China. CONCLUSIONS: Collectively, our findings indicate that the real-world effectiveness and economy of the SMART regimen are superior to the traditional strategies in pediatric asthma patients.

UPLC-MS based integrated plasma proteomic and metabolomic profiling of TSC-RAML and its relationship with everolimus treatment.

Aim: To profile the plasma proteomics and metabolomics of patients with renal cysts, sporadic angiomyolipoma (S-AML) and tuberous sclerosis complex related angiomyolipoma (TSC-RAML) before and after everolimus treatment, and to find potential diagnostic and prognostic biomarkers as well as reveal the underlying mechanism of TSC tumorigenesis. Materials and Methods: We retrospectively measured the plasma proteins and metabolites from November 2016 to November 2017 in a cohort of pre-treatment and post-treatment TSC-RAML patients and compared them with renal cyst and S-AML patients by ultra-performance liquid chromatography-mass spectrometer (UPLC-MS). The tumor reduction rates of TSC-RAML were assessed and correlated with the plasma protein and metabolite levels. In addition, functional analysis based on differentially expressed molecules was performed to reveal the underlying mechanisms. Results: Eighty-five patients with one hundred and ten plasma samples were enrolled in our study. Multiple proteins and metabolites, such as pre-melanosome protein (PMEL) and S-adenosylmethionine (SAM), demonstrated both diagnostic and prognostic effects. Functional analysis revealed many dysregulated pathways, including angiogenesis synthesis, smooth muscle proliferation and migration, amino acid metabolism and glycerophospholipid metabolism. Conclusion: The plasma proteomics and metabolomics pattern of TSC-RAML was clearly different from that of other renal tumors, and the differentially expressed plasma molecules could be used as prognostic and diagnostic biomarkers. The dysregulated pathways, such as angiogenesis and amino acid metabolism, may shed new light on the treatment of TSC-RAML.

Dynamic urine proteome changes in a rat model of simvastatin-induced skeletal muscle injury.

Statin-associated muscle symptoms (SAMS) are the main side effects of statins. Currently, there are no effective biomarkers for accurate clinical diagnosis. Urine is not subject to homeostatic control and therefore accumulates early changes, making it an ideal biomarker source. We therefore examined urine proteome changes associated with SAMS. Here, we established a SAMS rat model by intragastric intubation with simvastatin (80 mg/kg). Biochemical analyses and hematoxylin and eosin staining were used to evaluate the degree of muscle injury. The urine proteome on days 3, 6, 9 and 14 was profiled using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Differential proteins on day 14 of SAMS were mainly associated with glycolysis/gluconeogenesis, pyruvate metabolism, metabolism of reactive oxygen species and apoptosis, which were associated with the pathological mechanism of SAMS. Among the 14 differential proteins on day 3, Fibrinogen gamma chain (FIBG), Osteopontin (OSTP) and C-reactive protein (CRP) were associated with muscle damage, while EH domain-containing protein 1(EHD1), Cubilin (CUBN) and Fibronectin (FINC) were associated with the pathogenic mechanisms of SAMS. Our preliminary results indicated that the urine proteome can reflect early changes in the SAMS rat model, providing the potential for monitoring drug side effects in future clinical research. SIGNIFICANCE: This study demonstrate that the early muscle damage caused by simvastatin can be reflected in urinary proteins. The urine proteome also has the potential to reflect the pharmacology and toxicology of drugs in future clinical research.

Detection of pediatric drug-induced kidney injury signals using a hospital electronic medical record database.

Background: Drug-induced kidney injury (DIKI) is one of the most common complications in clinical practice. Detection signals through post-marketing approaches are of great value in preventing DIKI in pediatric patients. This study aimed to propose a quantitative algorithm to detect DIKI signals in children using an electronic health record (EHR) database. Methods: In this study, 12 years of medical data collected from a constructed data warehouse were analyzed, which contained 575,965 records of inpatients from 1 January 2009 to 31 December 2020. Eligible participants included inpatients aged 28 days to 18 years old. A two-stage procedure was adopted to detect DIKI signals: 1) stage 1: the suspected drugs potentially associated with DIKI were screened by calculating the crude incidence of DIKI events; and 2) stage 2: the associations between suspected drugs and DIKI were identified in the propensity score-matched retrospective cohorts. Unconditional logistic regression was used to analyze the difference in the incidence of DIKI events and to estimate the odds ratio (OR) and 95% confidence interval (CI). Potentially new signals were distinguished from already known associations concerning DIKI by manually reviewing the published literature and drug instructions. Results: Nine suspected drugs were initially screened from a total of 652 drugs. Six drugs, including diazepam (OR = 1.61, 95%CI: 1.43-1.80), omeprazole (OR = 1.35, 95%CI: 1.17-1.54), ondansetron (OR = 1.49, 95%CI: 1.36-1.63), methotrexate (OR = 1.36, 95%CI: 1.25-1.47), creatine phosphate sodium (OR = 1.13, 95%CI: 1.05-1.22), and cytarabine (OR = 1.17, 95%CI: 1.06-1.28), were demonstrated to be associated with DIKI as positive signals. The remaining three drugs, including vitamin K1 (OR = 1.06, 95%CI: 0.89-1.27), cefamandole (OR = 1.07, 95%CI: 0.94-1.21), and ibuprofen (OR = 1.01, 95%CI: 0.94-1.09), were found not to be associated with DIKI. Of these, creatine phosphate sodium was considered to be a possible new DIKI signal as it had not been reported in both adults and children previously. Moreover, three other drugs, namely, diazepam, omeprazole, and ondansetron, were shown to be new potential signals in pediatrics. Conclusion: A two-step quantitative procedure to actively explore DIKI signals using real-world data (RWD) was developed. Our findings highlight the potential of EHRs to complement traditional spontaneous reporting systems (SRS) for drug safety signal detection in a pediatric setting.

Mining Severe Drug Hypersensitivity Reaction Cases in Pediatric Electronic Health Records: Methodology Development and Applications.

BACKGROUND: Severe drug hypersensitivity reactions (DHRs) refer to allergic reactions caused by drugs and usually present with severe skin rashes and internal damage as the main symptoms. Reporting of severe DHRs in hospitals now solely occurs through spontaneous reporting systems (SRSs), which clinicians in charge operate. An automatic identification system scrutinizes clinical notes and reports potential severe DHR cases. OBJECTIVE: The goal of the research was to develop an automatic identification system for mining severe DHR cases and discover more DHR cases for further study. The proposed method was applied to 9 years of data in pediatrics electronic health records (EHRs) of Beijing Children's Hospital. METHODS: The phenotyping task was approached as a document classification problem. A DHR dataset containing tagged documents for training was prepared. Each document contains all the clinical notes generated during 1 inpatient visit in this data set. Document-level tags correspond to DHR types and a negative category. Strategies were evaluated for long document classification on the openly available National NLP Clinical Challenges 2016 smoking task. Four strategies were evaluated in this work: document truncation, hierarchy representation, efficient self-attention, and key sentence selection. In-domain and open-domain pretrained embeddings were evaluated on the DHR dataset. An automatic grid search was performed to tune statistical classifiers for the best performance over the transformed data. Inference efficiency and memory requirements of the best performing models were analyzed. The most efficient model for mining DHR cases from millions of documents in the EHR system was run. RESULTS: For long document classification, key sentence selection with guideline keywords achieved the best performance and was 9 times faster than hierarchy representation models for inference. The best model discovered 1155 DHR cases in Beijing Children's Hospital EHR system. After double-checking by clinician experts, 357 cases of severe DHRs were finally identified. For the smoking challenge, our model reached the record of state-of-the-art performance (94.1% vs 94.2%). CONCLUSIONS: The proposed method discovered 357 positive DHR cases from a large archive of EHR records, about 90% of which were missed by SRSs. SRSs reported only 36 cases during the same period. The case analysis also found more suspected drugs associated with severe DHRs in pediatrics.

Signal Detection of Pediatric Drug-Induced Coagulopathy Using Routine Electronic Health Records.

Background: Drug-induced coagulopathy (DIC) is a severe adverse reaction and has become a significantly increased clinical problem in children. It is crucial to the detection of the DIC safety signal for drug post-marketing scientific supervision purposes. Therefore, this study aimed to detect potential signals for DIC in children using the routine electronic medical record (EMR) data. Methods: This study extracted EMR data from Beijing Children's Hospital between 2009 and 2020. A two-stage modeling method was developed to detect the signal of DIC. We calculated the crude incidence by mining cases of coagulopathy to select the potential suspected drugs; then, propensity score-matched retrospective cohorts of specific screened drugs from the first stage were constructed and estimated the odds ratio (OR) and 95% confidence interval (CI) using conditional logistic regression models. The current literature evidence was used to assess the novelty of the signal. Results:In the study, from a total of 340 drugs, 22 drugs were initially screened as potentially inducing coagulopathy. In total, we identified 19 positive DIC associations. Of these, potential DIC risk of omeprazole (OR: 2.23, 95% CI: 1.88-2.65), chlorpheniramine (OR:3.04, 95% CI:2.56-3.60), and salbutamol sulfate (OR:1.36, 95% CI:1.07-1.73) were three new DIC signals in both children and adults. Twelve associations between coagulopathy and drugs, meropenem (OR: 3.38, 95% CI: 2.72-4.20), cefoperazone sulbactam (OR: 2.80, 95% CI: 2.30-3.41), fluconazole (OR: 2.11, 95% CI: 1.71-2.59), voriconazole (OR: 2.82, 95% CI: 2.20-3.61), ambroxol hydrochloride (OR: 2.12, 95% CI: 1.74-2.58), furosemide (OR: 2.36, 95% CI: 2.08-2.67), iodixanol (OR: 2.21, 95% CI: 1.72-2.85), cefamandole (OR: 1.82, 95% CI: 1.56-2.13), ceftizoxime (OR: 1.95, 95% CI: 1.44-2.63), ceftriaxone (OR: 1.95, 95% CI: 1.44-2.63), latamoxef sodium (OR: 1.76, 95% CI: 1.49-2.07), and sulfamethoxazole (OR: 1.29, 95% CI: 1.01-1.64), were considered as new signals in children. Conclusion: The two-stage algorithm developed in our study to detect safety signals of DIC found nineteen signals of DIC, including twelve new signals in a pediatric population. However, these safety signals of DIC need to be confirmed by further studies based on population study and mechanism research.

A multi­omics study of diagnostic markers and the unique inflammatory tumor micro­environment involved in tuberous sclerosis complex­related renal angiomyolipoma.

Tuberous sclerosis complex (TSC) is a rare disease that threatens multiple organs in the human body. TSC­associated renal angiomyolipoma (TSC­RAML) has potentially life­threatening complications and a generally poor prognosis. The present study aimed to find plasma proteomic diagnostics and disease­associated markers, and explore the tumor microenvironment using multi­omics. To achieve this goal, the plasma proteomics as well as tissue proteomics, bulk and single­cell RNA transcriptome from patients with TSC­RAML were examined and analyzed. The results suggested that plasma proteins such as MMP9 and C­C motif chemokine ligand 5 were able to differentiate TSC­RAML from sporadic angiomyolipoma and renal cyst. A correlation analysis revealed that plasma proteomics were associated with lymphangioleiomyomatosis, TSC­RAML grading and whole­body disease burden. Tissue proteomics of participants with TSC­RAML revealed disturbed small molecule catabolic process, mitochondrial matrix component and actin binding function. Bulk and single­cell RNA sequencing suggested a greater number of tumor­like cells, fibroblasts and mononuclear macrophages within the tumor microenvironment. The above results indicated that TSC­RAML exhibited a characteristic and disease­associated plasma proteomic profile. The unique microenvironment, made up of fibroblasts and mono­macrophages, may promote tumorigenesis and TSC­RAML progression.

Proteomic analysis of urine reveals biomarkers for the diagnosis and phenotyping of abdominal-type Henoch-Schonlein purpura.

BACKGROUND: Abdominal-type Henoch-Schonlein purpura (HSP) is a common refractory disease in children. Currently, no specific diagnostic biomarker is available for HSP. METHODS: Children with abdominal type HSP were first diagnosed with three syndromes using Chinese traditional medicine. The urinary proteomes among the three syndromes of patients with abdominal type HSP and healthy controls were compared using two label-free proteomics quantifications, including data-dependent acquisition and data-independent acquisition. RESULTS: For the comparison between patients with abdominal type HSP and healthy children, a total of 75 differential urinary proteins were identified by determining the overlap of the two experiments. The ingenuity pathway analysis (IPA) analysis showed that these differential proteins were correlated with the pathogenesis of abdominal type HSP. Of these, 37 proteins were distributed in 13 solid tissues as tissue-enriched proteins. Monitoring changes in these proteins might help us detect uncommon clinical manifestations of HSP. Patients with abdominal type HSP can be further distinguished into three syndromes based on the urine proteome. Finally, a panel of six urinary proteins (P25774, P09417, Q7Z5L0, P60900, P14550 and P09668) was constructed for both the diagnosis and phenotyping of abdominal type HSP. CONCLUSIONS: Urinary protein biomarkers for the diagnosis and phenotyping of abdominal type HSP were identified, which will contribute to the personalized treatment of patients with abdominal type HSP.

Detection of Drug-Induced Thrombocytopenia Signals in Children Using Routine Electronic Medical Records.

Background: Drug-induced thrombocytopenia (DITP) is a severe adverse reaction and a significantly under-recognized clinical problem in children. However, for post-marketing pharmacovigilance purposes, detection of DITP signals is crucial. This study aimed to develop a signal detection model for DITP using the pediatric electronic medical records (EMR) data. Methods: This study used the electronic medical records collected at Beijing Children's Hospital between 2009 and 2020. A two-stage modeling method was developed to detect the signal of DITP. In the first stage, we calculated the crude incidence by mining cases of thrombocytopenia to select the potential suspected drugs. In the second stage, we constructed propensity score-matched retrospective cohorts of specific screened drugs from the first stage and estimated the odds ratio (OR) and 95% confidence interval (CI) using conditional logistic regression models. The novelty of the signal was assessed by current evidence. Results: In the study, from a total of 839 drugs, 21 drugs were initially screened as potentially inducing thrombocytopenia. In total, we identified 18 positive DITP associations. Of these, potential DITP risk of nystatin (OR: 1.75, 95% CI: 1.37-2.22) and latamoxef sodium (OR: 1.61, 95% CI: 1.38-1.88) were two new DITP signals in both children and adults. Six associations between thrombocytopenia and drugs including imipenem (OR: 1.69, 95% CI: 1.16-2.45), teicoplanin (OR: 4.75, 95% CI: 3.33-6.78), fusidic acid (OR: 2.81, 95% CI: 2.06-3.86), ceftizoxime sodium (OR: 1.83, 95% CI: 1.36-2.45), ceftazidime (OR: 2.16, 95% CI: 1.58-2.95), and cefepime (OR: 5.06, 95% CI: 3.77-6.78) were considered as new signals in children. Conclusion: This study developed a two-stage algorithm to detect safety signals of DITP and found eighteen positive signals of DITP, including six new signals in a pediatric population. This method is a promising tool for pharmacovigilance based on EMR data.

Signal Detection of Potentially Drug-Induced Liver Injury in Children Using Electronic Health Records.

Background: This study proposes a quantitative 2-stage procedure to detect potential drug-induced liver injury (DILI) signals in pediatric inpatients using an data warehouse of electronic health records (EHRs). Methods: Eight years of medical data from a constructed database were used. A two-stage procedure was adopted: (i) stage 1: the drugs suspected of inducing DILI were selected and (ii) stage 2: the associations between the drugs and DILI were identified in a retrospective cohort study. Results: 1,196 drugs were filtered initially and 12 drugs were further potentially identified as suspect drugs inducing DILI. Eleven drugs (fluconazole, omeprazole, sulfamethoxazole, vancomycin, granulocyte colony-stimulating factor (G-CSF), acetaminophen, nifedipine, fusidine, oseltamivir, nystatin and meropenem) were showed to be associated with DILI. Of these, two drugs, nystatin [odds ratio[OR]=1.39, 95%CI:1.10-1.75] and G-CSF (OR = 1.91, 95%CI:1.55-2.35), were found to be new potential signals in adults and children. Three drugs [nifedipine [OR = 1.77, 95%CI:1.26-2.46], fusidine [OR = 1.43, 95%CI:1.08-1.86], and oseltamivi r [OR = 1.64, 95%CI:1.23-2.18]] were demonstrated to be new signals in pediatrics. The other drug-DILI associations had been confirmed in previous studies. Conclusions: A quantitative algorithm to detect potential signals of DILI has been described. Our work promotes the application of EHR data in pharmacovigilance and provides candidate drugs for further causality assessment studies.

Exploring the drug-induced anemia signals in children using electronic medical records.

Objectives: The objectives were to identify drugs related with anemia in children and evaluate the novelty of these correlations. Methods: The authors established a two-step method for detecting the relationship between drugs and anemia using electronic medical records (EMRs), which were obtained from 247,136 patients in Beijing Children's Hospital between 2007 and 2017. The authors extracted potential drugs by mining cases for hemoglobin abnormalities from the EMR and then performed a retrospective cohort study to correlate them with anemia by calculating the matched odds ratios and 95% confidence interval using unconditional logistic regression analysis. Results: In total, nine positive drug-anemia associations were identified. Among them, the correlations of drugs fluconazole (OR 3.95; 95%CI: 2.65-5.87) and cefathiamidine (OR 3.49; 95%CI: 2.94-4.15) with anemia were considered new signals in both children and adults. Three associations of drugs, vancomycin, cefoperazone-sulbactam and ibuprofen, with anemia were considered new signals in children. Conclusion: The authors detected nine signals of drug-induced anemia, including two new signals in children and adults and three new signals in children. This study could serve as a model for using EMR and automatic mining to monitor adverse drug reaction signals in the pediatric population.

Pediatric drug safety signal detection of non-chemotherapy drug-induced neutropenia and agranulocytosis using electronic healthcare records.

Objectives: This study aimed to develop a procedure to explore the adverse drug reaction signals of drug-induced neutropenia (DIN) or drug-induced agranulocytosis (DIA) in children using an electronic health records (EHRs) database. Methods: A two-stage design was presented. First, the suspected drugs to induce DIN or DIA were selected. Second, the associations were evaluated by a retrospective cohort study. Results: Ten and five drugs were potentially identified to be associated with DIN and DIA, respectively. Finally, five (oseltamivir, chlorpheniramine, vancomycin, meropenem, and ganciclovir) and two (chlorpheniramine, and vancomycin) drugs were found to be associated with DIN and DIA, respectively. Of these, the association between oseltamivir and neutropenia (P = 9.83 × 10-9; OR, 2.10; 95% CI, 1.62-2.69) was considered as a new signal for both adults and children. Chlorpheniramine-induced neutropenia (P = 3.01 × 10-8; OR, 1.59; 95% CI, 1.35-1.87) and agranulocytosis (P = 3.16 × 10-7; OR, 3.76; 95% CI, 2.25-6.26) were considered as new signals in children. Other drugs associated with DIN or DIA were confirmed by previous studies. Conclusion: A method to detect signals for DIN and DIA has been described. Several pediatric drugs were found to be associated with DIN or DIA.

Trough concentration of itraconazole and its relationship with efficacy and safety: a systematic review and meta-analysis.

OBJECTIVES: The optimum trough concentration of itraconazole for clinical response and safty is controversial. The objective of this systematic review and meta-analysis was to determine the optimum trough concentration of itraconazole and evaluate its relationship with efficacy and safety. METHODS: We searched PubMed, EMBASE, Web of Science, the Cochrane Library, Clinical-Trials.gov, and three Chinese literature databases (CNKI, WanFang, and CBM). We included observational studies that compared clinical outcomes below or above the trough concentration cut-off value which we set as 0.25, 0.5, and 1.0 mg/L. The efficacy outcomes were rate of successful treatment, rate of prophylaxis failure and invasive fungal infection (IFI)-related mortality. The safety outcomes included incidents of hepatotoxicity and other adverse events. RESULTS: The study included a total of 29 studies involving 2,346 patients. Our meta-analysis showed that compared with itraconazole trough concentrations (Ctrough) of ≥0.25 mg/L, levels of <0.25 mg/L significantly increased the incidence of IFI for prophylaxis (RR =3.279, 95% confidence interval [CI] 1.73-6.206). Moreover, the success rate of treatment decreased significantly at a cut-off level of 0.5 mg/L (RR =0.396, 95% CI 0.176-0.889). An itraconazole trough level of 1.0 mg/L was associated with hepatotoxicity and other adverse events in a review of many studies. CONCLUSION: An itraconazole trough concentration of 0.25 mg/L should be considered as the lower threshold for prophylaxis, and a target concentration of 0.5 mg/L should be the lower limit for effective treatment. A trough level of 1.0 mg/L is associated with increased hepatotoxicity and other adverse events (using High Performance Liquid Chromatography [HPLC]).

Association between HLA-B*15:02 and oxcarbazepine-induced cutaneous adverse reaction: a meta-analysis.

AIM: HLA-B*15:02 has been demonstrated as a key risk factor for carbamazepine-induced severe cutaneous adverse reaction (sCAR), especially in Asian population. Oxcarbazepine (OXC) is a drug that has a similar structure of carbamazepine. However, the relationship between HLA-B*15:02 and induced cutaneous adverse reaction (cADR) remains unknown. This study aims to analyze this association in the published literature. METHOD: After filtering studies, eight studies were finally included for meta-analysis, including 32 sCAR cases, 112 mild cutaneous adverse reaction (mcADR) cases, 281 OXC tolerant control and 946 population control cases. RESULT: In the tolerant control group, an association was found between HLA-B*15:02 genotype and OXC-induced sCAR (odds ratio [OR]: 18.13; 95% CI: 6.77-48.56), but not in mcADR (OR: 1.43; 95% CI: 0.56-3.64). In population control group, an association was found between HLA-B*15:02 genotype and OXC-induced sCAR, (OR: 8.22; 95% CI: 3.03-22.34), but not in mcADR (OR: 2.06; 95% CI: 0.91-4.67). DISCUSSION: Our study demonstrates that the genetic risk factor HLA-B*15:02 may be a factor in OXC-induced sCAR.