A pipeline for the fully automated estimation of continuous reference intervals using real-world data.

Reference intervals are essential for interpreting laboratory test results. Continuous reference intervals precisely capture physiological age-specific dynamics that occur throughout life, and thus have the potential to improve clinical decision-making. However, established approaches for estimating continuous reference intervals require samples from healthy individuals, and are therefore substantially restricted.

Pharmacokinetic-pharmacodynamic modeling of maintenance therapy for childhood acute lymphoblastic leukemia.

In the treatment of childhood acute lymphoblastic leukemia (ALL), current protocols combine initial high-dose multiagent chemotherapy with prolonged oral therapy with 6-mercaptopurine (6MP) and low-dose methotrexate (MTX) maintenance therapy. Decades of research on ALL treatment have resulted in survival rates of approximately 90%. However, dose-response relationships vary widely between patients and insight into the influencing factors, that would allow for improved personalized treatment management, is insufficient.

Temporal evolution and differential patterns of cellular reconstitution after therapy for childhood cancers.

The cellular reconstitution after childhood cancer therapy is associated with the risk of infection and efficacy of revaccination. Many studies have described the reconstitution after stem cell transplantation (SCT). The recovery after cancer treatment in children who have not undergone SCT has mainly been investigated in acute lymphoblastic leukemia (ALL), less for solid tumors.

RIbench: A Proposed Benchmark for the Standardized Evaluation of Indirect Methods for Reference Interval Estimation.

Background: Indirect methods leverage real-world data for the estimation of reference intervals. These constitute an active field of research, and several methods have been developed recently. So far, no standardized tool for evaluation and comparison of indirect methods exists.

Reference Intervals of Serum TSH from Mixed Distributions Using Truncation Points and the Kolmogorov-Smirnov Distance.

Background: Serum TSH reference intervals (RIs) are methodology, population, and age specific. However, the ethical and practical challenges restrict the establishment of pediatric RIs using conventional approaches and advocates the use of indirect data mining-based algorithms. This study was carried out to estimate the reference interval of neonatal serum TSH in Pakistani population using an indirect approach.

Mixture density networks for the indirect estimation of reference intervals.

Background: Reference intervals represent the expected range of physiological test results in a healthy population and are essential to support medical decision making. Particularly in the context of pediatric reference intervals, where recruitment regulations make prospective studies challenging to conduct, indirect estimation strategies are becoming increasingly important. Established indirect methods enable robust identification of the distribution of "healthy" samples from laboratory databases, which include unlabeled pathologic cases, but are currently severely limited when adjusting for essential patient characteristics such as age.

Differences between capillary and venous blood counts in children-A data mining approach.

Background: Capillary sampling of blood counts is a well-established alternative to venipuncture in paediatrics. However, the sampling method has to be considered when interpreting test results, as measurements differ. Ethical and practical considerations prevent simultaneous venous and capillary sample acquisition in comprehensive paediatric cohorts that span all ages for the purpose of a direct method comparison, resulting in uncertainty regarding the interpretation of capillary test results.

Age- and sex-specific pediatric reference intervals for neutrophil-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, and platelet-to-lymphocyte ratio.

Introduction: Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) are emerging biomarkers for systemic inflammation and have been shown to predict morbidity and mortality for several diseases. However, lack of pediatric reference intervals (RIs) prevents their comprehensive use in patient care and medical research.

Material And Methods: We calculated reference intervals and corresponding confidence intervals for NLR, PLR, and LMR from birth to 18 years using a data-mining approach: We analyzed 232 746 blood counts from 60 685 patients performed during patient care and excluded patients with elevated C-reactive protein and procalcitonin.

Influence of Turkish origin on hematology reference intervals in the German population.

Reference intervals for laboratory test results have to be appropriate for the population in which they are used to be clinically useful. While sex and age are established partitioning criteria, patients' origin also influences laboratory test results, but is not commonly considered when creating or applying reference intervals. In the German population, stratification for ethnicity is rarely performed, and no ethnicity-specific hematology reference intervals have been reported yet.

Quantification of Translocation-Specific ctDNA Provides an Integrating Parameter for Early Assessment of Treatment Response and Risk Stratification in Ewing Sarcoma.

Purpose: We evaluated the predictive and prognostic value of circulating tumor DNA (ctDNA) in patients with Ewing sarcoma (EWS) treated in the EWING2008 trial.

Experimental Design: Plasma samples from 102 patients with EWS enrolled in the EWING2008 trial were obtained before and during induction chemotherapy. Genomic fusion sequence spanning primers and probes were used for highly specific and sensitive quantification of the levels of ctDNA by digital droplet PCR.

refineR: A Novel Algorithm for Reference Interval Estimation from Real-World Data.

Reference intervals are essential for the interpretation of laboratory test results in medicine. We propose a novel indirect approach to estimate reference intervals from real-world data as an alternative to direct methods, which require samples from healthy individuals. The presented refineR algorithm separates the non-pathological distribution from the pathological distribution of observed test results using an inverse approach and identifies the model that best explains the non-pathological distribution.

Indirect determination of serum creatinine reference intervals in a Pakistani pediatric population using big data analytics.

Background: The indirect methods of reference intervals (RI) establishment based on data mining are utilized to overcome the ethical, practical challenges and the cost associated with the conventional direct approach.

Aim: To generate RIs for serum creatinine in children and adolescents using an indirect statistical tool.

Methods: Data mining of the laboratory information system was performed for serum creatinine analyzed from birth to 17 years for both genders.

First Steps to Evaluate an NLP Tool's Medication Extraction Accuracy from Discharge Letters.

Introduction: The aim of this study is to evaluate the use of a natural language processing (NLP) software to extract medication statements from unstructured medical discharge letters.

Methods: Ten randomly selected discharge letters were extracted from the data warehouse of the University Hospital Erlangen (UHE) and manually annotated to create a gold standard. The AHD NLP tool, provided by MIRACUM's industry partner was used to annotate these discharge letters.

A Multi-User Terminology Mapping Toolbox.

Semantic interoperability is a major challenge in multi-center data sharing projects, a challenge that the German Initiative for Medical Informatics is taking up. With respect to laboratory data, enriching site-specific tests and measurements with LOINC codes appears to be a crucial step in supporting cross-institutional research. However, this effort is very time-consuming, as it requires expert knowledge of local site specifics.

A Framework for Criteria-Based Selection and Processing of Fast Healthcare Interoperability Resources (FHIR) Data for Statistical Analysis: Design and Implementation Study.

Background: The harmonization and standardization of digital medical information for research purposes is a challenging and ongoing collaborative effort. Current research data repositories typically require extensive efforts in harmonizing and transforming original clinical data. The Fast Healthcare Interoperability Resources (FHIR) format was designed primarily to represent clinical processes; therefore, it closely resembles the clinical data model and is more widely available across modern electronic health records.

High-resolution pediatric reference intervals for 15 biochemical analytes described using fractional polynomials.

Objectives: Assessment of children's laboratory test results requires consideration of the extensive changes that occur during physiological development and result in pronounced sex- and age-specific dynamics in many biochemical analytes. Pediatric reference intervals have to account for these dynamics, but ethical and practical challenges limit the availability of appropriate pediatric reference intervals that cover children from birth to adulthood. We have therefore initiated the multi-center data-driven project (Next-Generation Pediatric Reference Intervals) to create pediatric reference intervals using data from laboratory information systems.

Latent class distributional regression for the estimation of non-linear reference limits from contaminated data sources.

Background: Medical decision making based on quantitative test results depends on reliable reference intervals, which represent the range of physiological test results in a healthy population. Current methods for the estimation of reference limits focus either on modelling the age-dependent dynamics of different analytes directly in a prospective setting or the extraction of independent distributions from contaminated data sources, e.g.

Model-Based Simulation of Maintenance Therapy of Childhood Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia is the most common malignancy in childhood. Successful treatment requires initial high-intensity chemotherapy, followed by low-intensity oral maintenance therapy with oral 6-mercaptopurine (6MP) and methotrexate (MTX) until 2-3 years after disease onset. However, intra- and inter-individual variability in the pharmacokinetics (PK) and pharmacodynamics (PD) of 6MP and MTX make it challenging to balance the desired antileukemic effects with undesired excessive myelosuppression during maintenance therapy.

Blood counts in adult and elderly individuals: defining the norms over eight decades of life.

The blood count is one of the most common tests used for health assessment. In elderly individuals, selection of a 'healthy' reference population for laboratory assessment is difficult due to the high prevalence of chronic morbidities, leading to uncertainty regarding appropriate reference intervals. In particular, age-specific lower haemoglobin reference limits to define anaemia are controversial.

Reference Interval Estimation from Mixed Distributions using Truncation Points and the Kolmogorov-Smirnov Distance (kosmic).

Appropriate reference intervals are essential when using laboratory test results to guide medical decisions. Conventional approaches for the establishment of reference intervals rely on large samples from healthy and homogenous reference populations. However, this approach is associated with substantial financial and logistic challenges, subject to ethical restrictions in children, and limited in older individuals due to the high prevalence of chronic morbidities and medication.

Establishment of Reference Intervals for Alkaline Phosphatase in Pakistani Children Using a Data Mining Approach.

Objective: To establish reference intervals (RIs) for alkaline phosphatase (ALP) levels in Pakistani children using an indirect data mining approach.

Methods: ALP levels analyzed on a Siemens Advia 1800 analyzer using the International Federation of Clinical Chemistry's photometric method for both inpatients and outpatients aged 1 to 17 years between January 2013 and December 2017, including patients from intensive care units and specialty units, were retrieved. RIs were calculated using a previously validated indirect algorithm developed by the German Society of Clinical Chemistry and Laboratory Medicine's Working Group on Guide Limits.

Resistance to antibacterial therapy in pediatric febrile urinary tract infections-a single-center analysis.

Background: Febrile urinary tract infections (UTIs) are common serious bacterial infections in childhood and require early diagnosis and antibacterial therapy. However, considerable uncertainty exists regarding the optimal antibacterial agent for primary treatment of pediatric UTIs. Additionally, patterns of susceptibility and resistance change over time and microbiological in vitro resistance is not necessarily associated with treatment failure.

Correction: KETOS: Clinical decision support and machine learning as a service - A training and deployment platform based on Docker, OMOP-CDM, and FHIR Web Services.

[This corrects the article DOI: 10.1371/journal.pone.