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      Development of a Multivariate Predictive Model to Estimate Ionized Calcium Concentration from Serum Biochemical Profile Results in Dogs

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          Abstract

          Background

          Ionized calcium concentration is the gold standard to assess calcium status in dogs, but measurement is not always available.

          Objectives

          (1) To predict ionized calcium concentration from biochemical results and compare the diagnostic performance of predicted ionized calcium concentration (piCa) to those of total calcium concentration ( tCa) and 2 corrected tCa formulas; and (2) to study the relationship between biochemical results and variation of measured ionized calcium concentration (miCa).

          Animals

          A total of 1,719 dogs with both miCa and biochemical profile results available.

          Methods

          Cross‐sectional study. Using 1,200 dogs, piCa was determined using a multivariate adaptive regression splines model. Its accuracy and performance were tested on the remaining 519 dogs.

          Results

          The final model included creatinine, albumin, tCa, phosphorus, sodium, potassium, chloride, alkaline phosphatase, triglycerides, and age, with tCa, albumin, and chloride having the highest impact on miCa variation. Measured ionized calcium concentration was better correlated with piCa than with tCa and corrected tCa and had higher overall diagnostic accuracy to diagnose hypocalcemia and hypercalcemia, but not significantly for hypercalcemia. For hypercalcemia, piCa was as sensitive (64%) but more specific (99.6%) than tCa and corrected tCa. For hypocalcemia, piCa was more sensitive (21.8%) and as specific (98.4%) as tCa. Positive and negative predictive values of piCa were high for both hypercalcemia (90% and 98%, respectively) and hypocalcemia (70.8% and 87.7%, respectively).

          Conclusions and clinical importance

          Predicted ionized calcium concentration can be obtained from readily available biochemical and patient results and seems more useful than tCa and corrected tCa to assess calcium disorders in dogs when miCa is unavailable. Validation on external data, however, is warranted.

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          Most cited references36

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          External validation is necessary in prediction research: a clinical example.

          G Derksen-Lubsen, K. G. M. Moons, Jonathan Bleeker … (2003)
          Prediction models tend to perform better on data on which the model was constructed than on new data. This difference in performance is an indication of the optimism in the apparent performance in the derivation set. For internal model validation, bootstrapping methods are recommended to provide bias-corrected estimates of model performance. Results are often accepted without sufficient regard to the importance of external validation. This report illustrates the limitations of internal validation to determine generalizability of a diagnostic prediction model to future settings. A prediction model for the presence of serious bacterial infections in children with fever without source was derived and validated internally using bootstrap resampling techniques. Subsequently, the model was validated externally. In the derivation set (n=376), nine predictors were identified. The apparent area under the receiver operating characteristic curve (95% confidence interval) of the model was 0.83 (0.78-0.87) and 0.76 (0.67-0.85) after bootstrap correction. In the validation set (n=179) the performance was 0.57 (0.47-0.67). For relatively small data sets, internal validation of prediction models by bootstrap techniques may not be sufficient and indicative for the model's performance in future patients. External validation is essential before implementing prediction models in clinical practice.
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            Functional hypoparathyroidism and parathyroid hormone end-organ resistance in human magnesium deficiency.

            R Rude, Christian F. Singer, Nicola Oldham (1976)
            Hypocalcaemia is a well-recognized manifestation of magnesium deficiency. We have studied seventeen patients with this syndrome in an attempt to determine the pathogenesis of the hypocalcaemia. Mean initial serum calcium concentration was 5-6 mg/dl and mean initial serum magnesium concentration was 0-75 mg/dl. Serum immunoreactive parathyroid hormone (IPTH) was measured in sixteen patients in the untreated state. Despite severe hypocalcaemia, serum IPTH was either undetectable (less than 150 pg/ml) or normal (less than 550 pg/ml) in all but two patients. Serial measurements made during the initial 4 days of magnesium therapy in four patients showed an increase in serum IPTH within 24h, but a delayed increase in serum calcium, which required approximately 4 days to reach normal values. The effect of the rapid normalization of serum magnesium on serum IPTH and serum calcium concentration was studied in three patients. Within 1 min after 144-300 mg of elemental magnesium was administered i.v., serum IPTH had risen from undetectable to 3600 pg/ml and 1725 pg/ml in two patients and from 425 pg/ml to 937 pg/ml in the third. Serum calcium concentrations were unchanged after 30-60 min. These data provide evidence for impaired parathyroid gland function in most of the magnesium deficient patients. The rapidity with which serum IPTH rose in response to magnesium therapy indicates that this may reflect a defect in parathyroid hormone (PTH) secretion rather than its biosynthesis. The failure of serum calcium concentration to increase during the initial days of magnesium repletion, at a time when serum IPTH concentrations were normal or elevated, suggests end-organ resistance to PTH in these patients. The renal response to PTH was examined in two magnesium deficient patients by measurement of urinary cyclic AMP excretion following administration of parathyroid extract. In both patients there was a minimal increase in urinary cyclic AMP concentrations. In contrast, when the hepatic response to glucagon was tested on the same patients by measurement of plasma cyclic AMP concentrations following administration of glucagon, normal increases were observed. These results suggest that adenylate cyclase systems of various organs may be affected differentially by a state of magnesium deficiency. It is suggested that magnesium deficiency may result in defective cyclic AMP generation in the parathyroid glands and in the PTH target organs. This could be the principal mechanism operative in both impaired PTH secretion and end-organ resistance to PTH which together contribute to the development of hypocalcaemia.
            Article 0 comments Cited 41 times – based on 0 reviews     Review now
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              Ionized calcium in normal serum, ultrafiltrates, and whole blood determined by ion-exchange electrodes.

              Sophie E. Moore (1970)
              Ion-exchange calcium electrodes represent the first practical method for the direct measurement of ionized calcium [Ca(++)] in biologic fluids. Using both "static" and "flow-through" electrodes, serum [Ca(++)] was within a rather narrow range: 0.94-1.33 mmoles/liter (mean, 1.14 mmoles/liter). Within a given individual, [Ca(++)] varied only about 6% over a several month period. Consistent pH effects on [Ca(++)] were observed in serum and whole blood, [Ca(++)] varying inversely with pH. Less consistent pH effects were also noted in ultrafiltrates, believed to largely represent precipitation of certain calcium complexes from a supersaturated solution. Heparinized whole blood [Ca(++)] was significantly less than in corresponding serum at normal blood pH, related to the formation of a calcium-heparin complex. [Ca(++)] in ultrafiltrates represented a variable fraction (66.7-90.2%) of total diffusible calcium. There was no apparent correlation between serum ionized and total calcium concentrations. Thus, neither serum total calcium nor total ultrafiltrable calcium provided a reliable index of serum [Ca(++)]. Change in serum total calcium was almost totally accounted for by corresponding change in protein-bound calcium [CaProt]. About 81% of [CaProt] was estimated to be bound to albumin and about 19% to globulins. From observed pH, serum protein, and [CaProt] data, a nomogram was developed for estimating [CaProt] without ultrafiltration. Data presented elsewhere indicate that calcium binding by serum proteins obeys the mass-law equation for a monoligand association. This was indicated in the present studies by a close correspondence of observed serum [Ca(++)] values with those predicted by the McLean-Hastings nomogram. While these electrodes allow study of numerous problems not possible previously, they have not been perfected to the same degree of reliability obtainable with current pH electrodes. The commercial (Orion flow-through) electrode is: (a) expensive. (b) requires periodic replacement of membranes, and (c) has not yet been thermostated. As with blood pH measurements. (d) electrode response is logarithmic, i.e. small potential errors generate rather large [Ca(++)] errors. (e) loss of CO(2) should be prevented, and (f) errors due to other cations must be considered under certain conditions. Despite these limitations, we believe the electrode represents a major advance in calcium metabolism.
              Article 0 comments Cited 35 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                K. Le Boedec:
                ORCID: http://orcid.org/0000-0002-8427-0520
                drleboedec@hotmail.fr
                Journal
                Journal ID (nlm-ta): J Vet Intern Med
                Journal ID (iso-abbrev): J. Vet. Intern. Med
                Journal ID (doi): 10.1111/(ISSN)1939-1676
                Journal ID (publisher-id): JVIM
                Title: Journal of Veterinary Internal Medicine
                Publisher: John Wiley and Sons Inc. (Hoboken )
                ISSN (Print): 0891-6640
                ISSN (Electronic): 1939-1676
                Publication date (Electronic): 20 August 2017
                Publication date (Print): Sep-Oct 2017
                Volume: 31
                Issue: 5 ( doiID: 10.1111/jvim.2017.31.issue-5 )
                Pages: 1392-1402
                Affiliations
                [ 1 ] University of Illinois Champaign‐Urbana College of Veterinary Medicine Urbana IL
                [ 2 ] Centre Hospitalier Vétérinaire Frégis Arcueil France
                Author notes
                [*] [* ]Corresponding author: Kevin Le Boedec, Centre Hospitalier Vétérinaire Frégis, 43 Avenue Aristide Briand, 94110 Arcueil, France; e‐mail: drleboedec@ 123456hotmail.fr
                Author information
                http://orcid.org/0000-0002-8427-0520
                Article
                Publisher ID: JVIM14800
                DOI: 10.1111/jvim.14800
                PMC ID: 5598902
                PubMed ID: 28833561
                SO-VID: 3b560352-7e10-496e-b11f-3017bcb82375
                Copyright © Copyright © 2017 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.
                License:

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                Date received : 26 January 2017
                Date revision received : 27 June 2017
                Date accepted : 13 July 2017
                Page count
                Figures: 3, Tables: 5, Pages: 11, Words: 9101
                Categories
                Subject: Standard Article
                Subject: SMALL ANIMAL
                Subject: Standard Articles
                Subject: Endocrinology
                Custom metadata
                source-schema-version-number 2.0
                component-id jvim14800
                cover-date September/October 2017
                details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_NLMPMC version:5.1.9 mode:remove_FC converted:14.09.2017

                ScienceOpen disciplines: Veterinary medicine
                Keywords: canine,hypercalcemia,hypocalcemia,prediction
                Data availability:
                ScienceOpen disciplines: Veterinary medicine
                Keywords: canine, hypercalcemia, hypocalcemia, prediction

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