Establishment of variation source and age-related reference interval models for 22 common biochemical analytes in older people using real-world big data mining

Abstract Background the ageing population has increased in many countries, including China. However, reference intervals (RIs) for older people are rarely established because of difficulties in selecting reference individuals. Here, we aimed to analyse the factors affecting biochemical analytes and establish RI and age-related RI models for biochemical analytes through mining real-world big data. Methods data for 97,220 individuals downloaded from electronic health records were included. Three derived databases were established. The first database included 97,220 individuals and was used to build age-related RI models after identifying outliers by the Tukey method. The second database consisted of older people and was used to establish variation source models and RIs for biochemical analytes. Differences between older and younger people were compared using the third database. Results sex was the main source of variation of biochemical analytes for older people in the variation source models. The distributions of creatinine and uric acid were significantly different in the RIs of biochemical analytes for older people established according to sex. Age-related RI models for biochemical analytes that were most affected by age were built and visualized, revealing various patterns of changes from the younger to older people. Conclusion the study analysed the factors affecting biochemical analytes in older people. Moreover, RI and age-related RI models of biochemical analytes for older people were established to provide important insight into biological processes and to assist clinical use of various biochemical analytes to monitor the status of various diseases for older people.

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Experience with the Urinary Tetrasaccharide Metabolite for Pompe Disease in the Diagnostic Laboratory

Metabolites ◽

10.3390/metabo11070446 ◽

2021 ◽

Vol 11 (7) ◽

pp. 446

Author(s):

Jennifer T. Saville ◽

Maria Fuller

Keyword(s):

Pompe Disease ◽

Late Onset ◽

Reference Interval ◽

Laboratory Diagnosis ◽

Reference Intervals ◽

Confirmatory Test ◽

Diagnostic Laboratory ◽

Age Related ◽

Initial Drop ◽

Monitoring Treatment

Following clinical indications, the laboratory diagnosis of the inherited metabolic myopathy, Pompe disease (PD), typically begins with demonstrating a reduction in acid alpha-glucosidase (GAA), the enzyme required for lysosomal glycogen degradation. Although simple in concept, a major challenge is defining reference intervals, as even carriers can have reduced GAA, and pseudodeficiencies complicate interpretation. Here, we developed a mass spectrometric assay for quantification of a urinary glycogen metabolite (tetrasaccharide) and reported on its utility as a confirmatory test for PD in a diagnostic laboratory. Using two age-related reference intervals, eight returned tetrasaccharide concentrations above the calculated reference interval but did not have PD, highlighting non-specificity. However, retrospective analysis revealed elevated tetrasaccharide in seven infantile-onset (IOPD) cases and sixteen late-onset (LOPD) cases, and normal concentrations in one heterozygote. Prospective tetrasaccharide analysis in nine individuals with reduced GAA confirmed IOPD in one, LOPD in six and identified two heterozygotes. Using this metabolite as a biomarker of therapeutic response was not overly informative; although most patients showed an initial drop following therapy initiation, tetrasaccharide concentrations fluctuated considerably and remained above reference intervals in all patients. While useful as a confirmation of PD, its utility as a biomarker for monitoring treatment warrants further investigation.

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NUMBER: standardized reference intervals in the Netherlands using a ‘big data’ approach

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2018-0462 ◽

2018 ◽

Vol 0 (0) ◽

Cited By ~ 1

Author(s):

Wendy P.J. den Elzen ◽

Nannette Brouwer ◽

Marc H. Thelen ◽

Saskia Le Cessie ◽

Inez-Anne Haagen ◽

...

Keyword(s):

General Chemistry ◽

Big Data ◽

The Netherlands ◽

Clinical Laboratory ◽

Reference Interval ◽

Clinical Decision ◽

Reference Intervals ◽

Test Results ◽

Study Population ◽

Set Up

AbstractBackgroundExternal quality assessment (EQA) programs for general chemistry tests have evolved from between laboratory comparison programs to trueness verification surveys. In the Netherlands, the implementation of such programs has reduced inter-laboratory variation for electrolytes, substrates and enzymes. This allows for national and metrological traceable reference intervals, but these are still lacking. We have initiated a national endeavor named NUMBER (Nederlandse UniforMe Beslisgrenzen En Referentie-intervallen) to set up a sustainable system for the determination of standardized reference intervals in the Netherlands.MethodsWe used an evidence-based ‘big-data’ approach to deduce reference intervals using millions of test results from patients visiting general practitioners from clinical laboratory databases. We selected 21 medical tests which are either traceable to SI or have Joint Committee for Traceability in Laboratory Medicine (JCTLM)-listed reference materials and/or reference methods. Per laboratory, per test, outliers were excluded, data were transformed to a normal distribution (if necessary), and means and standard deviations (SDs) were calculated. Then, average means and SDs per test were calculated to generate pooled (mean±2 SD) reference intervals. Results were discussed in expert meetings.ResultsSixteen carefully selected clinical laboratories across the country provided anonymous test results (n=7,574,327). During three expert meetings, participants found consensus about calculated reference intervals for 18 tests and necessary partitioning in subcategories, based on sex, age, matrix and/or method. For two tests further evaluation of the reference interval and the study population were considered necessary. For glucose, the working group advised to adopt the clinical decision limit.ConclusionsUsing a ‘big-data’ approach we were able to determine traceable reference intervals for 18 general chemistry tests. Nationwide implementation of these established reference intervals has the potential to improve unequivocal interpretation of test results, thereby reducing patient harm.

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The older person with diabetes: considerations for care

Practice Nursing ◽

10.12968/pnur.2019.30.6.282 ◽

2019 ◽

Vol 30 (6) ◽

pp. 282-286

Author(s):

Jill Hill

Keyword(s):

Renal Impairment ◽

Older People ◽

Health Professionals ◽

Diabetes Management ◽

Competency Assessment ◽

Ageing Population ◽

Older Person ◽

Glucose Lowering ◽

The Status ◽

The Uk

The UK has an ageing population more and more elderly people are living with diabetes. Jill Hill explores the condition as well as other healthcare challenges that comes with caring for this particular patient group With the increasingly ageing population worldwide, more older people are living with diabetes. The conditions that often accompany older age, such as dementia, renal impairment, visual impairment and manual dexterity difficulties, can make diabetes management complex and self-care challenging. However, the status of older people varies considerably, and so choice of glucose-lowering agents and clinical targets should be individualised to maximise safety and ensure that the risks of treatments do not outweigh the benefits. For many patients, there will be an increasing dependence on others to manage their diabetes care, therefore an appropriate skill mix among health professionals and carers, adequate training and regular competency assessment are crucial to support patients to remain safe and symptom free from diabetes.

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Albumin and calcium reference interval using healthy individuals and a data-mining approach

Annals of Clinical Biochemistry International Journal of Laboratory Medicine ◽

10.1177/0004563220944204 ◽

2020 ◽

Vol 57 (5) ◽

pp. 373-381 ◽

Cited By ~ 2

Author(s):

N Jassam ◽

A Luvai ◽

D Narayanan ◽

D Turnock ◽

G Lee ◽

...

Keyword(s):

Metrological Traceability ◽

Reference Interval ◽

Reference Population ◽

Reference Intervals ◽

Healthy Individuals ◽

Reference Limit ◽

Common Reference ◽

Age Related ◽

Upper Reference Limit ◽

Analytical Platforms

Background Harmonization of reference intervals for analytes that have a sound calibration and metrological traceability is a widely recommended practice. The UK Pathology Harmony has recently harmonized reference intervals for calcium and albumin. In this study, we have determined the reference intervals for calcium and albumin on the UK’s most commonly used analytical platforms. Method A prospective reference population of healthy individuals was recruited according to the IFCC CRIDL criteria. A second indirect population was collected from 14 primary care setting and measured in laboratories using various analytical platforms and methods (Roche, Abbott, Beckman and Siemens analytical platforms). Results In total, 299 subjects were recruited; the central 95th centile values for calcium for three out of four analytical platforms were in a close agreement with UK Pathology Harmony reference intervals of 2.2–2.6 mmol/L. Reference intervals of BCG methods from both cohorts and irrespective of analytical platforms were higher for both lower and upper reference limits than those for BCP. In comparison, the indirect study showed an age-related variation. The younger population reference intervals varied by up to 5.7% at the lower reference limit and up to 12% at the upper reference limit compared with Pathology Harmony reference intervals, and the older population showed a variation of up to 14% at both limits. Conclusion While calcium reference intervals can be a subject for harmonization, albumin reference intervals studied showed large variation which is unsupportive of embracing a common reference interval for albumin.

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Normal reference interval for thyrotropin response to thyroliberin: dependence on age, sex, free thyroxin index, and basal concentrations of thyrotropin.

Clinical Chemistry ◽

10.1093/clinchem/30.2.196 ◽

1984 ◽

Vol 30 (2) ◽

pp. 196-199 ◽

Cited By ~ 21

Author(s):

E M Erfurth ◽

N E Nordén ◽

P Hedner ◽

A Nilsson ◽

L Ek

Keyword(s):

Linear Regression Analysis ◽

Reference Interval ◽

Multiple Linear Regression Analysis ◽

Reference Intervals ◽

Multivariate Statistical Methods ◽

Individual Values ◽

Multivariate Statistical ◽

Normal Reference ◽

Age Related ◽

Basal Concentration

Abstract We measured the thyrotropin response (delta TSH) to 200 micrograms of thyroliberin in 131 subjects without thyroid dysfunction or other disease and with basal values for thyroid function that were within the normal reference intervals for our laboratory. By univariate and multivariate statistical methods we found delta TSH to be significantly influenced by the basal concentration of thyrotropin (TSH0) and the free thyroxin index (FT4I). When the effects of variations in TSH0 and FT4I were eliminated, delta TSH in men under 40 years of age did not differ from that in women. A decrease in delta TSH with increasing age was found in men but not in women. Thus a reference interval for delta TSH should consider TSH0, FT4I, and, in men, age. On the basis of multiple linear regression analysis, we constructed a formula for delta TSH reference intervals that takes into account individual values for TSH0 and FT4I. The formula should be applicable for women, regardless of age, up to 77 years and for men under 40 years. For older men a correction for the age-related decrease in delta TSH must be applied.

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Ageing, immunity and influenza: a role for probiotics?

Proceedings of The Nutrition Society ◽

10.1017/s0029665113003777 ◽

2013 ◽

Vol 73 (2) ◽

pp. 309-317 ◽

Cited By ~ 21

Author(s):

Parveen Yaqoob

Keyword(s):

Gut Microbiota ◽

Older People ◽

Influenza A ◽

Respiratory Infections ◽

Ageing Population ◽

Susceptibility To Infection ◽

Age Related ◽

Randomised Controlled ◽

Adjuvant Effects ◽

The Impact

Influenza is a major cause of death in the over 65s. Increased susceptibility to infection and reduced response to vaccination are due to immunosenscence in combination with medical history and lifestyle factors. Age-related alterations in the composition of the gut microbiota have a direct impact on the immune system and it is proposed that modulation of the gut microbiota using pre- and probiotics could offer an opportunity to improve immune responses to infections and vaccination in older people. There is growing evidence that probiotics have immunomodulatory properties, which to some extent are strain-dependent, and are strongly influenced by ageing. Randomised controlled trials suggest that probiotics may reduce the incidence and/or severity of respiratory infections, although there is limited data on older people. A small number of studies have examined the potential adjuvant effects of selected probiotics for vaccination against influenza; however, the data is inconsistent, particularly in older people. This review describes the impact of age-related changes in the gut on the immune response to respiratory infections and evaluates whether restoration of gut microbial homoeostasis by probiotics offers an opportunity to modulate the outcome of respiratory infections and vaccination against influenza in older people. Although there is promising evidence for effects of probiotics on human health, there is a lack of consistent data, perhaps partly due to strain-specific differences and an influence of the age of the host. Further research is critical in evaluating the potential use of probiotics in respiratory infections and vaccination in the ageing population.

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Age-related reference values for urinary excretion of sialic acid and deoxysialic acid: application to diagnosis of storage disorders of free sialic acid

Clinical Chemistry ◽

10.1093/clinchem/41.4.544 ◽

1995 ◽

Vol 41 (4) ◽

pp. 544-547 ◽

Cited By ~ 9

Author(s):

J Romppanen ◽

I Mononen

Keyword(s):

Sialic Acid ◽

Urinary Excretion ◽

Reference Values ◽

Reference Interval ◽

Reference Intervals ◽

Mean Value ◽

Hplc Method ◽

Age Related ◽

Free Sialic Acid ◽

Storage Disorders

Abstract We have established by HPLC age-related reference intervals for sialic acid urinary excretion in 364 control individuals to assist in evaluating the clinical significance of the free sialic acid concentration in urine. In addition, an HPLC method for quantitative analysis of free deoxysialic acid was developed, and age-related reference intervals for excretion of this compound in urine were established. In patients with storage disorders of free sialic acid (n = 11) the sialic acid excretion was increased 2- to 35-fold, compared with the mean value of the control subjects in the corresponding age group, and exceeded the interval in each case. The excretion of deoxysialic acid was within the reference interval in all of the patients, indicating that its metabolism was not affected in the disorders. The age-related reference values assist in evaluating the excretion of free sialic acid in the diagnosis of storage disorders of free sialic acid, especially in young children.

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Nomogram of age-specific anti-Müllerian hormone levels in healthy Egyptian females

PLoS ONE ◽

10.1371/journal.pone.0254858 ◽

2021 ◽

Vol 16 (7) ◽

pp. e0254858

Author(s):

Eman Ahmed El-Attar ◽

Tamer A. Hosny ◽

Kiyoshi Ichihara ◽

Rania N. Bedair ◽

Ahmed Salah El-Din Tork

Keyword(s):

Reference Interval ◽

Reference Intervals ◽

Specific Reference ◽

Clinical Settings ◽

Power Transformation ◽

Serum Samples ◽

Female Age ◽

Age Related ◽

Age Dependent ◽

Age Range

Background Anti-Müllerian hormone (AMH) is an important determinant of ovarian reserve in fertility workups in many clinical settings. Thus, we investigated the age dependent decline in AMH specific to the Egyptian population and sought to establish an age dependent reference interval parametrically. Methods Serum samples were collected from 841 apparently healthy women. AMH was measured using an electro-chemiluminescent technique. Box-Cox power transformation was used to make the AMH distribution Gaussian for parametric derivation of reference intervals. Results Power of 0.4 was found optimal for Gaussian transformation of AMH reference values. We demonstrate the strong negative relation between circulating AMH and female age with Spearman’s correlation coefficient of rS = −0.528. Age-specific reference interval was determined for every 5 years of age from 16 to 49, and nomogram was constructed by smoothing the lines connecting adjacent lower and upper reference limits. Conclusion The age-specific reference intervals and the age-AMH nomogram could be valuable in the clinical practice of in reproductive medicine. To our knowledge, this is the first study to confirm AMH levels in Egyptian females. We were able to explore age-related AMH levels specific to Egyptian females in the fertile age group and to treat skewed AMH data in a multi-step scheme using power transformation. Thus, a more accurate nomogram was constructed accommodating a profile delineated for a wide age range and a rescaled AMH axis improving its usability.

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Difficulties in establishing reference intervals for special fluids: the example of 5-hydroxyindoleacetic acid and homovanillic acid in cerebrospinal fluids

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm.2004.137 ◽

2004 ◽

Vol 42 (7) ◽

Cited By ~ 4

Author(s):

Jean-Louis Dhondt

Keyword(s):

Cerebrospinal Fluid ◽

Homovanillic Acid ◽

Reference Interval ◽

Reference Intervals ◽

Control Group ◽

Age Related ◽

Wide Range ◽

Hydroxyindoleacetic Acid ◽

Biochemical Measurements

AbstractBiochemical measurements in “special fluids” are complicated with the problem of reference intervals. Reference intervals are difficult to establish for these types of samples since they are usually only collected in patients with clinical suspicion of disease. Determination of neurotransmitter metabolites in cerebrospinal fluid illustrates this difficulty. This paper will review the factors and circumstances that have been identified or are suspected to modifythe concentration of 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) in cerebrospinal fluid. In addition to obvious parameters such as age-related variation that can affect the concentration of 5-HIAA and HVA in cerebrospinal fluid, a varietyof other factors can explain the wide range of “control” group sizes reported in the literature. Reference intervals must take into account the purpose of cerebrospinal fluid examinations, whether they be prospective studies to explore physio-pathologic relationships or for diagnostic purposes. In the latter case, certain neurological disorders cannot be excluded if a single measured value is within the reference interval.

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Determination of reference intervals for serum magnesium

Clinical Chemistry ◽

10.1093/clinchem/36.5.756 ◽

1990 ◽

Vol 36 (5) ◽

pp. 756-758 ◽

Cited By ~ 8

Author(s):

G O Duncanson ◽

H G Worth

Keyword(s):

Alkaline Phosphatase ◽

Gaussian Distribution ◽

Parametric Analysis ◽

Serum Magnesium ◽

Reference Interval ◽

Reference Intervals ◽

Age Related ◽

Reference Limits ◽

Males And Females

Abstract Using a discrete analyzer and a dye-binding method, we measured magnesium in 800 patients' samples received for routine analysis. By excluding data from samples for which the calcium and (or) alkaline phosphatase values were outside defined reference limits, we established a reference interval for magnesium. Because the data showed a gaussian distribution, we could use parametric analysis to establish age-related intervals for both males and females.

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