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  • 1
    Online Resource
    Online Resource
    Latent class distributional regression for the estimation of non-linear reference limits from contaminated data sources
    Springer Science and Business Media LLC ; 2020
    In:  BMC Bioinformatics Vol. 21, No. 1 ( 2020-12)
    Details
    In: BMC Bioinformatics, Springer Science and Business Media LLC, Vol. 21, No. 1 ( 2020-12)
    Abstract: 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. data with latent heterogeneity due to unlabeled pathologic cases. In this article, we propose a new method to estimate indirect reference limits with non-linear dependencies on covariates from contaminated datasets by combining the framework of mixture models and distributional regression. Results Simulation results based on mixtures of Gaussian and gamma distributions suggest accurate approximation of the true quantiles that improves with increasing sample size and decreasing overlap between the mixture components. Due to the high flexibility of the framework, initialization of the algorithm requires careful considerations regarding appropriate starting weights. Estimated quantiles from the extracted distribution of healthy hemoglobin concentration in boys and girls provide clinically useful pediatric reference limits similar to solutions obtained using different approaches which require more samples and are computationally more expensive. Conclusions Latent class distributional regression models represent the first method to estimate indirect non-linear reference limits from a single model fit, but the general scope of applications can be extended to other scenarios with latent heterogeneity.
    Type of Medium: Online Resource
    ISSN: 1471-2105
    URL: Article
    DOI: 10.1186/s12859-020-03853-3
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 2041484-5
    SSG: 12
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  • 2
    Online Resource
    Online Resource
    Reference Interval Estimation from Mixed Distributions using Truncation Points and the Kolmogorov-Smirnov Distance (kosmic)
    Springer Science and Business Media LLC ; 2020
    In:  Scientific Reports Vol. 10, No. 1 ( 2020-02-03)
    Details
    In: Scientific Reports, Springer Science and Business Media LLC, Vol. 10, No. 1 ( 2020-02-03)
    Abstract: 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. We implemented an indirect method for reference interval estimation, which uses mixed physiological and abnormal test results from clinical information systems, to overcome these restrictions. The algorithm minimizes the difference between an estimated parametrical distribution and a truncated part of the observed distribution, specifically, the Kolmogorov-Smirnov-distance between a hypothetical Gaussian distribution and the observed distribution of test results after Box-Cox-transformation. Simulations of common laboratory tests with increasing proportions of abnormal test results show reliable reference interval estimations even in challenging simulation scenarios, when 〈 20% test results are abnormal. Additionally, reference intervals generated using samples from a university hospital’s laboratory information system, with a gradually increasing proportion of abnormal test results remained stable, even if samples from units with a substantial prevalence of pathologies were included. A high-performance open-source C++ implementation is available at https://gitlab.miracum.org/kosmic .
    Type of Medium: Online Resource
    ISSN: 2045-2322
    URL: Article
    DOI: 10.1038/s41598-020-58749-2
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 2615211-3
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  • 3
    Online Resource
    Online Resource
    Blood counts in adult and elderly individuals: defining the norms over eight decades of life
    Wiley ; 2020
    In:  British Journal of Haematology Vol. 189, No. 4 ( 2020-05), p. 777-789
    Details
    In: British Journal of Haematology, Wiley, Vol. 189, No. 4 ( 2020-05), p. 777-789
    Abstract: 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. Here, we applied a data mining approach to a large dataset of 3 029 904 clinical routine samples to establish blood count reference intervals. We excluded samples from units/specialists with a high proportion of abnormal blood counts, samples from patients with an unknown or decreased estimated glomerular filtration rate, and samples with abnormal test results in selected other analytes. After sample exclusion, 566 775–572 060 samples from different individuals aged 20–100 years were available for analysis. We then used an established statistical algorithm to determine the distribution of physiological test results and calculated age‐ and sex‐specific reference intervals. Our results show substantial trends with age in haematology analytes' reference intervals. Most notably, haemoglobin and red cell counts decline in men with advanced age, accompanied by increases in red cell volume in both sexes. These findings were confirmed in an independent dataset, and suggest an at least partly physiologic cause.
    Type of Medium: Online Resource
    ISSN: 0007-1048 , 1365-2141
    URL: Issue
    URL: Article
    DOI: 10.1111/bjh.v189.4
    DOI: 10.1111/bjh.16430
    RVK:
    XA 34100
    Language: English
    Publisher: Wiley
    Publication Date: 2020
    detail.hit.zdb_id: 1475751-5
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  • 4
    Online Resource
    Online Resource
    Data mining of pediatric reference intervals
    Walter de Gruyter GmbH ; 2021
    In:  Journal of Laboratory Medicine Vol. 45, No. 6 ( 2021-12-20), p. 311-317
    Details
    In: Journal of Laboratory Medicine, Walter de Gruyter GmbH, Vol. 45, No. 6 ( 2021-12-20), p. 311-317
    Abstract: Laboratory tests are essential to assess the health status and to guide patient care in individuals of all ages. The interpretation of quantitative test results requires availability of appropriate reference intervals, and reference intervals in children have to account for the extensive physiological dynamics with age in many biomarkers. Creation of reference intervals using conventional approaches requires the sampling of healthy individuals, which is opposed by ethical and practical considerations in children, due to the need for a large number of blood samples from healthy children of all ages, including neonates and young infants. This limits the availability and quality of pediatric reference intervals, and ultimately negatively impacts pediatric clinical decision-making. Data mining approaches use laboratory test results and clinical information from hospital information systems to create reference intervals. The extensive number of available test results from laboratory information systems and advanced statistical methods enable the creation of pediatric reference intervals with an unprecedented age-related accuracy for children of all ages. Ongoing developments regarding the availability and standardization of electronic medical records and of indirect statistical methods will further improve the benefit of data mining for pediatric reference intervals.
    Type of Medium: Online Resource
    ISSN: 2567-9449 , 2567-9430
    URL: Article
    DOI: 10.1515/labmed-2021-0120
    Language: English
    Publisher: Walter de Gruyter GmbH
    Publication Date: 2021
    detail.hit.zdb_id: 2909042-8
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  • 5
    Online Resource
    Online Resource
    Age‐ and sex‐specific pediatric reference intervals for neutrophil‐to‐lymphocyte ratio, lymphocyte‐to‐monocyte ratio, and platelet‐to‐lymphocyte ratio
    Wiley ; 2022
    In:  International Journal of Laboratory Hematology Vol. 44, No. 2 ( 2022-04), p. 296-301
    Details
    In: International Journal of Laboratory Hematology, Wiley, Vol. 44, No. 2 ( 2022-04), p. 296-301
    Abstract: 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. Test results were separated according to age and sex, and the distribution of physiological ratios was estimated using an indirect approach ( refineR ). Additionally, we investigated the ratios’ diagnostic benefit for different inflammatory diseases (acute appendicitis, asthma, Bell's palsy, Henoch‐Schonlein purpura, and cystic fibrosis) using the newly obtained reference intervals. Results We estimated age‐ and sex‐specific reference intervals from birth to adulthood for NLR, PLR, and LMR. Analyses in pediatric inflammatory diseases showed that PLR and LMR were poor markers to detect the examined inflammatory diseases, while NLR was significantly increased in patients with appendicitis and asthma. Conclusion We provide pediatric reference intervals for NLR, PLR, and LMR to improve the interpretation of these biomarkers in children.
    Type of Medium: Online Resource
    ISSN: 1751-5521 , 1751-553X
    URL: Issue
    URL: Article
    DOI: 10.1111/ijlh.v44.2
    DOI: 10.1111/ijlh.13768
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2268600-9
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  • 6
    Online Resource
    Online Resource
    Pulmonary Dysfunction after Pediatric COVID-19
    Radiological Society of North America (RSNA) ; 2023
    In:  Radiology Vol. 306, No. 3 ( 2023-03-01)
    Details
    In: Radiology, Radiological Society of North America (RSNA), Vol. 306, No. 3 ( 2023-03-01)
    Type of Medium: Online Resource
    ISSN: 0033-8419 , 1527-1315
    URL: Article
    DOI: 10.1148/radiol.221250
    RVK:
    XA 10000
    Language: English
    Publisher: Radiological Society of North America (RSNA)
    Publication Date: 2023
    detail.hit.zdb_id: 80324-8
    detail.hit.zdb_id: 2010588-5
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  • 7
    Online Resource
    Online Resource
    Pediatric reference intervals for alkaline phosphatase
    Walter de Gruyter GmbH ; 2017
    In:  Clinical Chemistry and Laboratory Medicine (CCLM) Vol. 55, No. 1 ( 2017-1-1), p. 102-110
    Details
    In: Clinical Chemistry and Laboratory Medicine (CCLM), Walter de Gruyter GmbH, Vol. 55, No. 1 ( 2017-1-1), p. 102-110
    Abstract: Interpretation of alkaline phosphatase activity in children is challenging due to extensive changes with growth and puberty leading to distinct sex- and age-specific dynamics. Continuous percentile charts from birth to adulthood allow accurate consideration of these dynamics and seem reasonable for an analyte as closely linked to growth as alkaline phosphatase. However, the ethical and practical challenges unique to pediatric reference intervals have restricted the creation of such percentile charts, resulting in limitations when clinical decisions are based on alkaline phosphatase activity. Methods: We applied an indirect method to generate percentile charts for alkaline phosphatase activity using clinical laboratory data collected during the clinical care of patients. A total of 361,405 samples from 124,440 patients from six German tertiary care centers and one German laboratory service provider measured between January 2004 and June 2015 were analyzed. Measurement of alkaline phosphatase activity was performed on Roche Cobas analyzers using the IFCC’s photometric method. Results: We created percentile charts for alkaline phosphatase activity in girls and boys from birth to 18 years which can be used as reference intervals. Additionally, data tables of age- and sex-specific percentile values allow the incorporation of these results into laboratory information systems. Conclusions: The percentile charts provided enable the appropriate differential diagnosis of changes in alkaline phosphatase activity due to disease and changes due to physiological development. After local validation, integration of the provided percentile charts into result reporting facilitates precise assessment of alkaline phosphatase dynamics in pediatrics.
    Type of Medium: Online Resource
    ISSN: 1437-4331 , 1434-6621
    URL: Article
    DOI: 10.1515/cclm-2016-0318
    Language: English
    Publisher: Walter de Gruyter GmbH
    Publication Date: 2017
    detail.hit.zdb_id: 1492732-9
    SSG: 15,3
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  • 8
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    Online Resource
    Next-generation reference intervals for pediatric hematology
    Walter de Gruyter GmbH ; 2019
    In:  Clinical Chemistry and Laboratory Medicine (CCLM) Vol. 57, No. 10 ( 2019-09-25), p. 1595-1607
    Details
    In: Clinical Chemistry and Laboratory Medicine (CCLM), Walter de Gruyter GmbH, Vol. 57, No. 10 ( 2019-09-25), p. 1595-1607
    Abstract: Interpreting hematology analytes in children is challenging due to the extensive changes in hematopoiesis that accompany physiological development and lead to pronounced sex- and age-specific dynamics. Continuous percentile charts from birth to adulthood allow accurate consideration of these dynamics. However, the ethical and practical challenges unique to pediatric reference intervals have restricted the creation of such percentile charts, and limitations in current approaches to laboratory test result displays restrict their use when guiding clinical decisions. Methods We employed an improved data-driven approach to create percentile charts from laboratory data collected during patient care in 10 German centers (9,576,910 samples from 358,292 patients, 412,905–1,278,987 samples per analyte). We demonstrate visualization of hematology test results using percentile charts and z-scores (www.pedref.org/hematology) and assess the potential of percentiles and z-scores to support diagnosis of different hematological diseases. Results We created percentile charts for hemoglobin, hematocrit, red cell indices, red cell count, red cell distribution width, white cell count and platelet count in girls and boys from birth to 18 years of age. Comparison of pediatricians evaluating complex clinical scenarios using percentile charts versus conventional/tabular representations shows that percentile charts can enhance physician assessment in selected example cases. Age-specific percentiles and z-scores, compared with absolute test results, improve the identification of children with blood count abnormalities and the discrimination between different hematological diseases. Conclusions The provided reference intervals enable precise assessment of pediatric hematology test results. Representation of test results using percentiles and z-scores facilitates their interpretation and demonstrates the potential of digital approaches to improve clinical decision-making.
    Type of Medium: Online Resource
    ISSN: 1437-4331 , 1434-6621
    URL: Article
    DOI: 10.1515/cclm-2018-1236
    Language: English
    Publisher: Walter de Gruyter GmbH
    Publication Date: 2019
    detail.hit.zdb_id: 1492732-9
    SSG: 15,3
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  • 9
    Online Resource
    Online Resource
    Indirect determination of pediatric blood count reference intervals
    Walter de Gruyter GmbH ; 2013
    In:  Clinical Chemistry and Laboratory Medicine (CCLM) Vol. 51, No. 4 ( 2013-04-01), p. 863-872
    Details
    In: Clinical Chemistry and Laboratory Medicine (CCLM), Walter de Gruyter GmbH, Vol. 51, No. 4 ( 2013-04-01), p. 863-872
    Abstract: Background: Determination of pediatric reference intervals (RIs) for laboratory quantities, including hematological quantities, is complex. The measured quantities vary by age, and obtaining samples from healthy children is difficult. Many widely used RIs are derived from small sample numbers and are split into arbitrary discrete age intervals. Use of intra-laboratory RIs specific to the examined population and analytical device used is not yet fully established. Indirect methods address these issues by deriving RIs from clinical laboratory databases which contain large datasets of both healthy and pathological samples. Methods: A refined indirect approach was used to create continuous age-dependent RIs for blood count quantities and sodium from birth to adulthood. The dataset for each quantity consisted of 60,000 individual samples from our clinical laboratory. Patient samples were separated according to age, and a density function of the proportion of healthy samples was estimated for each age group. The resulting RIs were merged to obtain continuous RIs from birth to adulthood. Results: The obtained RIs were compared to RIs generated by identical laboratory instruments, and to population-specific RIs created using conventional methods. This comparison showed a high concordance of reference limits and their age-dependent dynamics. Conclusions: The indirect approach reported here is well-suited to create continuous, intra-laboratory RIs from clinical laboratory databases and showed that the RIs generated are comparable to those created using established methods. The procedure can be transferred to other laboratory quantities and can be used as an alternative method for RI determination where conventional approaches are limited.
    Type of Medium: Online Resource
    ISSN: 1437-4331 , 1434-6621
    URL: Article
    DOI: 10.1515/cclm-2012-0684
    Language: English
    Publisher: Walter de Gruyter GmbH
    Publication Date: 2013
    detail.hit.zdb_id: 1492732-9
    SSG: 15,3
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  • 10
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    Online Resource
    High-resolution pediatric reference intervals for 15 biochemical analytes described using fractional polynomials
    Walter de Gruyter GmbH ; 2021
    In:  Clinical Chemistry and Laboratory Medicine (CCLM) Vol. 59, No. 7 ( 2021-06-25), p. 1267-1278
    Details
    In: Clinical Chemistry and Laboratory Medicine (CCLM), Walter de Gruyter GmbH, Vol. 59, No. 7 ( 2021-06-25), p. 1267-1278
    Abstract: 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 PEDREF project (Next-Generation Pediatric Reference Intervals) to create pediatric reference intervals using data from laboratory information systems. Methods We analyzed laboratory test results from 638,683 patients (217,883–982,548 samples per analyte, a median of 603,745 test results per analyte, and 10,298,067 test results in total) performed during patient care in 13 German centers. Test results from children with repeat measurements were discarded, and we estimated the distribution of physiological test results using a validated statistical approach ( kosmic ). Results We report continuous pediatric reference intervals and percentile charts for alanine transaminase, aspartate transaminase, lactate dehydrogenase, alkaline phosphatase, γ-glutamyl-transferase, total protein, albumin, creatinine, urea, sodium, potassium, calcium, chloride, anorganic phosphate, and magnesium. Reference intervals are provided as tables and fractional polynomial functions (i.e., mathematical equations) that can be integrated into laboratory information systems. Additionally, Z -scores and percentiles enable the normalization of test results by age and sex to facilitate their interpretation across age groups. Conclusions The provided reference intervals and percentile charts enable precise assessment of laboratory test results in children from birth to adulthood. Our findings highlight the pronounced dynamics in many biochemical analytes in neonates, which require particular consideration in reference intervals to support clinical decision making most effectively.
    Type of Medium: Online Resource
    ISSN: 1437-4331 , 1434-6621
    URL: Article
    DOI: 10.1515/cclm-2020-1371
    Language: English
    Publisher: Walter de Gruyter GmbH
    Publication Date: 2021
    detail.hit.zdb_id: 1492732-9
    SSG: 15,3
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