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  • 1
    Online Resource
    Online Resource
    Elsevier BV ; 2019
    In:  Clinica Chimica Acta Vol. 499 ( 2019-12), p. 108-114
    In: Clinica Chimica Acta, Elsevier BV, Vol. 499 ( 2019-12), p. 108-114
    Type of Medium: Online Resource
    ISSN: 0009-8981
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2019
    detail.hit.zdb_id: 1499920-1
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  • 2
    Online Resource
    Online Resource
    Springer Science and Business Media LLC ; 2022
    In:  BMC Bioinformatics Vol. 23, No. 1 ( 2022-12)
    In: BMC Bioinformatics, Springer Science and Business Media LLC, Vol. 23, No. 1 ( 2022-12)
    Abstract: 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. Here, we propose the use of mixture density networks (MDN) to overcome this problem and model all parameters of the mixture distribution in a single step. Results Estimated reference intervals from varying settings with simulated data demonstrate the ability to accurately estimate latent distributions from unlabeled data using different implementations of MDNs. Comparing the performance with alternative estimation approaches further highlights the importance of modeling the mixture component weights as a function of the input in order to avoid biased estimates for all other parameters and the resulting reference intervals. We also provide a strategy to generate partially customized starting weights to improve proper identification of the latent components. Finally, the application on real-world hemoglobin samples provides results in line with current gold standard approaches, but also suggests further investigations with respect to adequate regularization strategies in order to prevent overfitting the data. Conclusions Mixture density networks provide a promising approach capable of extracting the distribution of healthy samples from unlabeled laboratory databases while simultaneously and explicitly estimating all parameters and component weights as non-linear functions of the covariate(s), thereby allowing the estimation of age-dependent reference intervals in a single step. Further studies on model regularization and asymmetric component distributions are warranted to consolidate our findings and expand the scope of applications.
    Type of Medium: Online Resource
    ISSN: 1471-2105
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2041484-5
    SSG: 12
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  • 3
    In: Molecular and Cellular Pediatrics, Springer Science and Business Media LLC, Vol. 4, No. S1 ( 2017-5)
    Type of Medium: Online Resource
    ISSN: 2194-7791
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2017
    detail.hit.zdb_id: 2785551-X
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  • 4
    In: Oncotarget, Impact Journals, LLC, Vol. 9, No. 41 ( 2018-05-29), p. 26543-26555
    Type of Medium: Online Resource
    ISSN: 1949-2553
    URL: Issue
    Language: English
    Publisher: Impact Journals, LLC
    Publication Date: 2018
    detail.hit.zdb_id: 2560162-3
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  • 5
    Online Resource
    Online Resource
    Springer Science and Business Media LLC ; 2020
    In:  BMC Bioinformatics Vol. 21, No. 1 ( 2020-12)
    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
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 2041484-5
    SSG: 12
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  • 6
    Online Resource
    Online Resource
    Oxford University Press (OUP) ; 2020
    In:  Laboratory Medicine Vol. 51, No. 5 ( 2020-09-01), p. 484-490
    In: Laboratory Medicine, Oxford University Press (OUP), Vol. 51, No. 5 ( 2020-09-01), p. 484-490
    Abstract: 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. Results From a total of 108,845 results, after the exclusion of patients with multiple specimens, RIs were calculated for 24,628 males and 18,083 females with stratification into fine-grained age groups. These RIs demonstrate the complex age- and sex-related ALP dynamics occurring during physiological development. Conclusion The population-specific RIs serve to allow an accurate understanding of the fluctuations in analyte activity with increasing age and to support clinical decision making.
    Type of Medium: Online Resource
    ISSN: 0007-5027 , 1943-7730
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
    detail.hit.zdb_id: 2100869-3
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  • 7
    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
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 2615211-3
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  • 8
    Online Resource
    Online Resource
    Springer Science and Business Media LLC ; 2023
    In:  Scientific Reports Vol. 13, No. 1 ( 2023-08-18)
    In: Scientific Reports, Springer Science and Business Media LLC, Vol. 13, No. 1 ( 2023-08-18)
    Abstract: 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. Indirect methods operating on routine measurements enable the estimation of one-dimensional reference intervals, however, no automated approach exists that integrates the dependency on a continuous covariate like age. We propose an integrated pipeline for the fully automated estimation of continuous reference intervals expressed as a generalized additive model for location, scale and shape based on discrete model estimates using an indirect method (refineR). The results are free of subjective user-input, enable conversion of test results into z-scores and can be integrated into laboratory information systems. Comparison of our results to established and validated reference intervals from the CALIPER and PEDREF studies and manufacturers’ package inserts shows good agreement of reference limits, indicating that the proposed pipeline generates high-quality results. In conclusion, the developed pipeline enables the generation of high-precision percentile charts and continuous reference intervals. It represents the first parameter-less and fully automated solution for the indirect estimation of continuous reference intervals.
    Type of Medium: Online Resource
    ISSN: 2045-2322
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 2615211-3
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  • 9
    In: Scientific Reports, Springer Science and Business Media LLC, Vol. 13, No. 1 ( 2023-03-10)
    Abstract: 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. Here, we have examined the temporal evolution of total leukocyte, neutrophil and lymphocyte counts as surrogate parameters for the post-therapeutic immune recovery in a cohort of n = 52 patients with ALL in comparison to n = 58 patients with Hodgkin’s disease (HD) and n = 22 patients with Ewing sarcoma (ES). Patients with ALL showed an efficient increase in blood counts reaching the age-adjusted lower limits of normal between 4 and 5 months after the end of maintenance therapy. The two groups of patients with HD and ES exhibited a comparably delayed recovery of total leukocytes due to a protracted post-therapeutic lymphopenia which was most pronounced in patients with HD after irradiation. Overall, we observed a clearly more efficient resurgence of total lymphocyte counts in patients aged below 12 years compared to patients aged 12 to 18 years. Our results underline that the kinetics of cellular reconstitution after therapy for HD and ES differ significantly from ALL and depend on treatment regimens and modalities as well as on patient age. This suggests a need for disease, treatment, and age specific recommendations concerning the duration of infection prophylaxis and the timing of revaccination.
    Type of Medium: Online Resource
    ISSN: 2045-2322
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 2615211-3
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  • 10
    In: Clinical Laboratory, Clinical Laboratory Publications, Vol. 68, No. 07/2022 ( 2022)
    Type of Medium: Online Resource
    ISSN: 1433-6510
    Language: English
    Publisher: Clinical Laboratory Publications
    Publication Date: 2022
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