Relative criticalness of common laboratory tests for critical value reporting.

We determined the relative strengths of association between 23 most commonly ordered laboratory tests and the adverse outcome as indicators of relative criticalness. The lowest and highest results for 23 most commonly ordered laboratory tests, 24 hours prior to death during critical care unit (CCU) stay or discharge from CCU were extracted from a publicly available CCU database (Medical Information Mart for Intensive Care-III). Following this, the Random Forest model was applied to assess the association between the laboratory results and the outcomes (death or discharge). The mean decrease in Gini coefficient for each laboratory test was then ranked as an indication of their relative importance to the outcome of a patient. In descending order, the 10 laboratory tests with the strongest association with death were: bicarbonate, phosphate, anion gap, white cell count (total), partial thromboplastin time, platelet, total calcium, chloride, glucose and INR; moreover, the strength of association was different for critically high versus low results.

An automated and objective method for age partitioning of reference intervals based on continuous centile curves.

Reference intervals are the most commonly used decision support tool when interpreting quantitative laboratory results. They may require partitioning to better describe subpopulations that display significantly different reference values. Partitioning by age is particularly important for the paediatric population since there are marked physiological changes associated with growth and maturation. However, most partitioning methods are either technically complex or require prior knowledge of the underlying physiology/biological variation of the population. There is growing interest in the use of continuous centile curves, which provides seamless laboratory reference values as a child grows, as an alternative to rigidly described fixed reference intervals. However, the mathematical functions that describe these curves can be complex and may not be easily implemented in laboratory information systems. Hence, the use of fixed reference intervals is expected to continue for a foreseeable time. We developed a method that objectively proposes optimised age partitions and reference intervals for quantitative laboratory data (http://research.sph.nus.edu.sg/pp/ppResult.aspx), based on the sum of gradient that best describes the underlying distribution of the continuous centile curves. It is hoped that this method may improve the selection of age intervals for partitioning, which is receiving increasing attention in paediatric laboratory medicine.

Trends and physiology of common serum biochemistries in children aged 0-18 years.

The aim of this study was to visually present and discuss in detail the physiological trends of 22 serum biochemistries in children aged 0-18.A data-mining, LMS (lambda, mu, and sigma) approach was employed to derive the smoothed continuous serum biochemistry centile charts, after application of stringent outlier exclusion criteria.Serum sodium and calculated osmolality are low in early life and rise with age due to maturing kidney and body water redistribution. Urea, creatinine and uric acid is high at birth, declines to reach a trough by 1 month of age and gradually rises again thereafter. Serum bicarbonate falls initially during the neonatal and toddler period, then rises with declining respiratory rate, further increasing sodium and suppressing chloride. Potassium, calcium and phosphate are required for somatic growth and are actively accrued during periods of rapid growth. Albumin increases until puberty while globulin rises to age 10 as a result of increased hepatic synthetic capacity and maturing immunity. Serum alkaline phosphatase activity peaks during bone growth spurts in infancy and adolescence due to osteoblast leakage, while creatinine increases with muscle mass. Serum gamma-glutamyl transferase, aspartate aminotransferase and lactate dehydrogenase activities are high at birth and decline with age. Serum alanine aminotransferase activity is low at birth and is induced by increased gluconeogenesis. Serum bilirubin increases continuously with age, mirroring haemoglobin concentration. Serum total cholesterol declines more markedly in boys than girls during puberty due to the combined effects of free testosterone (lowering high-density lipoprotein cholesterol in boys) and oestradiol (lowering low-density lipoprotein cholesterol in boys and girls).It is important to understand trends and biological variation when interpreting results since partitioned reference intervals may mask this information.

Indirect estimation of pediatric between-individual biological variation data for 22 common serum biochemistries.

OBJECTIVES: Derivation of between-individual biological variation (CVg) data requires repeat sampling of the same subject, which is undesirable and challenging in children. We describe an indirect sampling (data mining) approach to obtain these data in children. METHODS: Twenty-two serum biochemistry results from 6,989 children, who visited their primary care physician in Queensland, Australia, and were tested only twice within a year were included. The CVg and index of individuality of the boys and girls were estimated by year of age, according to the procedures recommended by Fraser and Harris. RESULTS: The CVg was generally higher during the first year of life and declined to reach a constant level by age 4 to 6 years, except for aspartate aminotransferase, alanine aminotransferase, γ-glutamyltransferase, and phosphate. The CVg for these tended to increase after age 10 years. Most of the serum biochemistries examined in this study had indices of individuality 0.6 or less, except sodium, anion gap, bicarbonate, and chloride, which ranged from 0.6 to 1.4. The indices of individuality were very stable across all ages. CONCLUSIONS: These data are comparable to those reported by the Canadian Laboratory Initiative on Pediatric Reference Intervals study and the Ricos database for adults. This study reports the CVg trends and data for boys and girls by year of age, which have not been described previously.

Paediatric reference interval and biological variation trends of thyrotropin (TSH) and free thyroxine (T4) in an Asian population.

AIMS: To describe the reference intervals and biological variation data for thyrotropin (TSH) and free thyroxine (FT4) in a mixed Asian population using an indirect sampling approach and to compare them with published reports. METHODS: TSH and FT4 of children measured once or twice over a 7-year period (2008-2014) at primary-care and tertiary-care settings were extracted from the laboratory information system. After excluding outliers, age-related reference intervals were derived using the Lambda-Mu-Sigma (LMS) approach, while age-partitioned biological variation data were obtained according to recommendations by Fraser and Harris. RESULTS: Both TSH and FT4 were very high at birth and declined with age. Similarly within-individual and between-individual biological variations were higher for both TSH and FT4 at birth and also declined with age. Our data were broadly similar to previous studies. Significant heterogeneity in study population and methods prohibited direct numerical comparison between this and previously published studies. CONCLUSIONS: This study fills two important gaps in our knowledge of paediatric thyroid function by reporting the centile trends (and reference values) in a mixed Asian population, as well as providing age-partitioned biological variation data. The variation in published reference intervals highlights the difficulty in harmonising paediatric thyroid reference intervals or recommending universal clinical cut-offs.

Derivation of pediatric within-individual biological variation by indirect sampling method: an LMS approach.

OBJECTIVES: Pediatric within-individual biological variation (CVi) is a challenge to derive by direct sampling due to clinical, logistical, and ethical barriers. METHODS: Laboratory results of 22 basic biochemistry tests performed on 9,356 children who visited primary care physicians more than once over a year were obtained from a large laboratory network in Australia. The CVi were calculated as (CVT (2) - CVa (2))(0.5), where CVT was the coefficient of variation between repeat measurements and CVa was the analytical imprecision. Smoothed 50th centile (median) CVi charts were derived using the LMS ChartMaker Light software (Medical Research Council, Cambridge, England) with L, M, and S parameters fixed at 3.0, 3.0, and 3.0 equivalent degrees of freedom, respectively. RESULTS: In general, the median CVi trends for this pediatric cohort remained relatively stable with increasing age. Only aspartate aminotransferase, globulin, phosphate, urea, and creatinine had differences between the highest and lowest median CVi of more than 30%. The differences between the child and adult CVi were relatively small. Nearly all the analytes had child to adult CVi ratios of 1.0 ± 0.5. CONCLUSIONS: The median CVi derived from patients with only two repeat biochemistry measurements may be considered reasonable estimates of CVi among children seeking treatment at primary care settings. The LMS approach allowed visualization of the continuous trends of CVi with age and extended the pediatric CVi estimation to younger than 4 years.