A new indirect estimation of reference intervals: truncated minimum chi-square (TMC) approach

2019 ◽  
Vol 57 (12) ◽  
pp. 1933-1947 ◽  
Author(s):  
Werner Wosniok ◽  
Rainer Haeckel
Keyword(s):  
Detection Limit ◽  
Simulated Data ◽  
Reference Interval ◽  
Reference Intervals ◽  
Skewed Data ◽  
Chi Square ◽  
Indirect Methods ◽  
Indirect Estimation ◽  
Estimated Parameters ◽  
Data Files

Abstract All known direct and indirect approaches for the estimation of reference intervals (RIs) have difficulties in processing very skewed data with a high percentage of values at or below the detection limit. A new model for the indirect estimation of RIs is proposed, which can be applied even to extremely skewed data distributions with a relatively high percentage of data at or below the detection limit. Furthermore, it fits better to some simulated data files than other indirect methods. The approach starts with a quantile-quantile plot providing preliminary estimates for the parameters (λ, μ, σ) of the assumed power normal distribution. These are iteratively refined by a truncated minimum chi-square (TMC) estimation. The finally estimated parameters are used to calculate the 95% reference interval. Confidence intervals for the interval limits are calculated by the asymptotic formula for quantiles, and tolerance limits are determined via bootstrapping. If age intervals are given, the procedure is applied per age interval and a spline function describes the age dependency of the reference limits by a continuous function. The approach can be performed in the statistical package R and on the Excel platform.

scholarly journals Diurnal variation of leukocyte counts affects the indirect estimation of reference intervals

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Antje Torge ◽  
Rainer Haeckel ◽  
Mustafa Özcürümez ◽  
Alexander Krebs ◽  
Ralf Junker
Keyword(s):  
Diurnal Variation ◽  
Indirect Method ◽  
Venous Blood ◽  
Direct Methods ◽  
Reference Intervals ◽  
Indirect Methods ◽  
Indirect Estimation ◽  
Late Afternoon ◽  
Reference Limits ◽  
Leukocyte Counts

Abstract It has been observed that the estimation of reference intervals of leukocytes in whole venous blood leads to higher upper reference limits (uRLs) with indirect methods than has been reported in the literature determined by direct approaches. This phenomenon was reinvestigated with a newer, more advanced indirect method, and could be confirmed. Furthermore, a diurnal variation was observed with lower values during the morning and higher values in the late afternoon and at night. This observation can explain why indirect approaches using samples collected during 24 h lead to higher uRLs than direct methods applied on samples collected presumably in the morning.

scholarly journals Indirect methods for reference interval determination – review and recommendations

2018 ◽  
Vol 0 (0) ◽  
Author(s):  
Graham R.D. Jones ◽  
Rainer Haeckel ◽  
Tze Ping Loh ◽  
Ken Sikaris ◽  
Thomas Streichert ◽  
...  
Keyword(s):  
Clinical Chemistry ◽  
Direct Methods ◽  
Analytical Techniques ◽  
Reference Interval ◽  
Reference Population ◽  
Reference Intervals ◽  
Statistical Techniques ◽  
Indirect Methods ◽  
Indirect Approach ◽  
Patient Health

Abstract Reference intervals are a vital part of the information supplied by clinical laboratories to support interpretation of numerical pathology results such as are produced in clinical chemistry and hematology laboratories. The traditional method for establishing reference intervals, known as the direct approach, is based on collecting samples from members of a preselected reference population, making the measurements and then determining the intervals. An alternative approach is to perform analysis of results generated as part of routine pathology testing and using appropriate statistical techniques to determine reference intervals. This is known as the indirect approach. This paper from a working group of the International Federation of Clinical Chemistry (IFCC) Committee on Reference Intervals and Decision Limits (C-RIDL) aims to summarize current thinking on indirect approaches to reference intervals. The indirect approach has some major potential advantages compared with direct methods. The processes are faster, cheaper and do not involve patient inconvenience, discomfort or the risks associated with generating new patient health information. Indirect methods also use the same preanalytical and analytical techniques used for patient management and can provide very large numbers for assessment. Limitations to the indirect methods include possible effects of diseased subpopulations on the derived interval. The IFCC C-RIDL aims to encourage the use of indirect methods to establish and verify reference intervals, to promote publication of such intervals with clear explanation of the process used and also to support the development of improved statistical techniques for these studies.

scholarly journals Application of the TML method to big data analytics and reference interval harmonization

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Mary Kathryn Bohn ◽  
Khosrow Adeli
Keyword(s):  
Clinical Chemistry ◽  
A Priori ◽  
Big Data Analytics ◽  
Reference Interval ◽  
German Society ◽  
Reference Intervals ◽  
Indirect Methods ◽  
Advantages And Disadvantages ◽  
Result Interpretation ◽  
Indirect Reference

Abstract Significant variation in reported reference intervals across healthcare centers and networks for many well-standardized laboratory tests continues to exist, negatively impacting patient outcomes by increasing the risk of inappropriate and inconsistent test result interpretation. Reference interval harmonization has been limited by challenges associated with direct reference interval establishment as well as hesitancies to apply currently available indirect methodologies. The Truncated Maximum Likelihood (TML) method for indirect reference interval establishment developed by the German Society of Clinical Chemistry and Laboratory Medicine (DGKL) presents unique clinical and statistical advantages compared to traditional indirect methods (Hoffmann and Bhattacharya), increasing the feasibility of developing indirect reference intervals that are comparable to those determined using a direct a priori approach based on healthy reference populations. Here, we review the application of indirect methods, particularly the TML method, to reference interval harmonization and discuss their associated advantages and disadvantages. We also describe the CSCC Reference Interval Harmonization Working Group’s experience with the application of the TML method in harmonization of adult reference intervals in Canada.

scholarly journals Age- and sex-dependent reference intervals for uric acid estimated by the truncated minimum chi-square (TMC) approach, a new indirect method

2020 ◽  
Vol 44 (3) ◽  
pp. 157-163
Author(s):  
Rainer Haeckel ◽  
Werner Wosniok ◽  
Antje Torge ◽  
Ralf Junker
Keyword(s):  
Uric Acid ◽  
Diurnal Variation ◽  
Acid Concentration ◽  
Metabolic Diseases ◽  
Age Groups ◽  
Reference Interval ◽  
Reference Intervals ◽  
Uric Acid Concentration ◽  
Chi Square ◽  
Age And Sex

Abstract Background Although the concentration of uric acid in serum or plasma is known to depend on sex and age and is subject to diurnal variation, the influence of these covariates on the reference interval (RI) is often neglected. Consequently, the values in the literature vary considerably. Therefore, we reinvestigated the reference limits and their dependence on covariates. Methods A new indirect approach was applied which derives a continuous function between age and RIs avoiding the usual “jumps” between various age groups. Results It is confirmed that the uric acid concentration in women is lower than in men. The RIs increase with age, in women more than in men. Between 80 and 90 years of age, the upper RI limit (RL) approximately reaches the same level in both sexes. Because the uric acid concentration may indicate renal insufficiency, the concentrations of creatinine and cystatin C were also measured. Both measurands showed the same behaviour as uric acid. Therefore, the age and sex dependency should be considered if the uric acid concentration is used as an indicator for hyperuricaemia (e.g. caused by gout or other metabolic diseases). Furthermore, a diurnal variation was observed. Conclusions Due to the variations of various covariates (age, sex, daytime, analytical systems), it is recommended that each laboratory should estimate its own RIs.

EXPRESS: Method dependent variation in TSH and FT4 reference intervals in pregnancy: a systematic review

2021 ◽  
pp. 000456322110269
Author(s):  
O E Okosieme ◽  
Medha Agrawal ◽  
Danyal Usman ◽  
Carol Evans
Keyword(s):  
Systematic Review ◽  
Reference Interval ◽  
First Trimester ◽  
Reference Intervals ◽  
Assay Method ◽  
Specific Reference ◽  
Upper Limits ◽  
Wide Range ◽  
Assay Methods ◽  
In Pregnancy

Background: Gestational TSH and FT4 reference intervals may differ according to assay method but the extent of variation is unclear and has not been systematically evaluated. We conducted a systematic review of published studies on TSH and FT4 reference intervals in pregnancy. Our aim was to quantify method-related differences in gestation reference intervals, across four commonly used assay methods, Abbott, Beckman, Roche, and Siemens. Methods: We searched the literature for relevant studies, published between January 2000 and December 2020, in healthy pregnant women without thyroid antibodies or disease. For each study, we extracted trimester-specific reference intervals (2.5–97.5 percentiles) for TSH and FT4 as well as the manufacturer provided reference interval for the corresponding non-pregnant population. Results: TSH reference intervals showed a wide range of study-to-study differences with upper limits ranging from 2.33 to 8.30 mU/L. FT4 lower limits ranged from 4.40–13.93 pmol/L, with consistently lower reference intervals observed with the Beckman method. Differences between non-pregnant and first trimester reference intervals were highly variable, and for most studies the TSH upper limit in the first trimester could not be predicted or extrapolated from non-pregnant values. Conclusions: Our study confirms significant intra and inter-method disparities in gestational thyroid hormone reference intervals. The relationship between pregnant and non-pregnant values is inconsistent and does not support the existing practice in some laboratories of extrapolating gestation references from non-pregnant values. Laboratories should invest in deriving method-specific gestation reference intervals for their population.

Evaluation of Thyroid Function in Pregnant Women Using Automated Immunoassays

2021 ◽  
Author(s):  
K Aaron Geno ◽  
Matthew S Reed ◽  
Mark A Cervinski ◽  
Robert D Nerenz
Keyword(s):  
Pregnant Women ◽  
Equilibrium Dialysis ◽  
Reference Interval ◽  
First Trimester ◽  
Reference Intervals ◽  
Free Thyroxine ◽  
Specific Reference ◽  
Childbearing Age ◽  
Thyroid Autoantibody ◽  
The Impact

Abstract Introduction Automated free thyroxine (FT4) immunoassays are widely available, but professional guidelines discourage their use in pregnant women due to theoretical under-recoveries attributed to increased thyroid hormone binding capacity and instead advocate the use of total T4 (TT4) or free thyroxine index (FTI). The impact of this recommendation on the classification of thyroid status in apparently euthyroid pregnant patients was evaluated. Methods After excluding specimens with thyroid autoantibody concentrations above reference limits, thyroid-stimulating hormone (TSH), FT4, TT4, and T-uptake were measured on the Roche Cobas® platform in remnant clinical specimens from at least 147 nonpregnant women of childbearing age and pregnant women at each trimester. Split-sample comparisons of FT4 as measured by the Cobas and equilibrium dialysis were performed. Results FT4 decreased with advancing gestational age by both immunoassay and equilibrium dialysis. TSH declined during the first trimester, remained constant in the second, and increased throughout the third, peaking just before delivery. Interpretation of TT4 concentrations using 1.5-times the nonpregnant reference interval classified 13.6% of first trimester specimens below the lower reference limit despite TSH concentrations within trimester-specific reference intervals. Five FTI results from 480 pregnant individuals (about 1.0%) fell outside the manufacturer’s reference interval. Conclusions Indirect FT4 immunoassay results interpreted in the context of trimester-specific reference intervals provide a practical and viable alternative to TT4 or FTI. Declining FT4 and increasing TSH concentrations near term suggest that declining FT4 is not an analytical artifact but represents a true physiological change in preparation for labor and delivery.

scholarly journals Reference values of plasma homocysteine in Cuban children and adults

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Alina Concepción Alvarez ◽  
Ivette Camayd Viera ◽  
Lisy Vento Buigues ◽  
Yanet Fernández Martínez ◽  
Eraida Hernández ◽  
...  
Keyword(s):  
Reference Values ◽  
High Performance ◽  
Age Groups ◽  
Coffee Consumption ◽  
Reference Interval ◽  
Reference Intervals ◽  
Multifactorial Diseases ◽  
Weak Association ◽  
Different Populations ◽  
Cuban Population

AbstractObjectivesHomocysteine (Hcy) is a nonessential amino acid, produced by the demethylation of methionine. High Hcy levels, or hyperhomocysteinemia, have been associated with genetic and multifactorial diseases. Hcy reference values may vary between different populations, as Hcy levels are affected by factors such as sex, age, diet, smoking, and coffee consumption. The estimation reference interval (RI) allows to establish the normal values of this marker in population. At present, these levels are unknown in Cuba. The aim of this work is to estimate the Hcy reference intervals in Cuban children and adults.MethodsTotal Hcy concentration was quantified by high performance liquid chromatography (HPLC) in plasma. Hcy levels were evaluated in samples from 507 healthy individuals (260 children, 247 adults).ResultsRIs were estimated by nonparametric methods. We found significant differences between both age groups, but we did not find significant differences between sexes, within these groups. The established ranges were 2.56–14.55 µM and 3.63–17.19 µM for children and adults, respectively. Also, we observed a weak association between Hcy levels and age in both sex groups.ConclusionsThis is the first study that assesses Hcy reference values in Cuban population. Our results will allow the introduction of Hcy as a biochemical marker in laboratory testing.

Reference intervals for venous blood gas measurement in adults

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Kirsty L. Ress ◽  
Gus Koerbin ◽  
Ling Li ◽  
Douglas Chesher ◽  
Phillip Bwititi ◽  
...  
Keyword(s):  
Partial Pressure ◽  
Meta Analysis ◽  
Venous Blood ◽  
Reference Interval ◽  
Reference Intervals ◽  
Published Data ◽  
Blood Gas ◽  
Arterial Blood Gas ◽  
Arterial Blood ◽  
Venous Blood Gas

AbstractObjectivesVenous blood gas (VBG) analysis is becoming a popular alternative to arterial blood gas (ABG) analysis due to reduced risk of complications at phlebotomy and ease of draw. In lack of published data, this study aimed to establish reference intervals (RI) for correct interpretation of VBG results.MethodsOne hundred and 51 adult volunteers (101 females, 50 males 18–70 y), were enrolled after completion of a health questionnaire. Venous blood was drawn into safePICO syringes and analysed on ABL827 blood gas analyser (Radiometer Pacific Pty. Ltd.). A non-parametric approach was used to directly establish the VBG RI which was compared to a calculated VBG RI based on a meta-analysis of differences between ABG and VBGResultsAfter exclusions, 134 results were used to derive VBG RI: pH 7.30–7.43, partial pressure of carbon dioxide (pCO2) 38–58 mmHg, partial pressure of oxygen (pO2) 19–65 mmHg, bicarbonate (HCO3−) 22–30 mmol/L, sodium 135–143 mmol/L, potassium 3.6–4.5 mmol/L, chloride 101–110 mmol/L, ionised calcium 1.14–1.29 mmol/L, lactate 0.4–2.2 mmol/L, base excess (BE) −1.9–4.5 mmol/L, saturated oxygen (sO2) 23–93%, carboxyhaemoglobin 0.4–1.4% and methaemoglobin 0.3–0.9%. The meta-analysis revealed differences between ABG and VBG for pH, HCO3−, pCO2 and pO2 of 0.032, −1.0 mmol/L, −4.2 and 39.9 mmHg, respectively. Using this data along with established ABG RI, calculated VBG RI of pH 7.32–7.42, HCO3− 23 – 27 mmol/L, pCO2 36–49 mmHg (Female), pCO2 39–52 mmHg (Male) and pO2 43–68 mmHg were formulated and compared to the VBG RI of this study.ConclusionsAn adult reference interval has been established to assist interpretation of VBG results.

Are the currently used reference intervals for creatine kinase (CK) reflecting the general population? The Tromsø Study

2012 ◽  
Vol 50 (5) ◽  
Author(s):  
Hallvard Lilleng ◽  
Stein Harald Johnsen ◽  
Tom Wilsgaard ◽  
Svein Ivar Bekkelund
Keyword(s):  
Creatine Kinase ◽  
General Population ◽  
Reference Interval ◽  
Reference Intervals ◽  
Control Analysis ◽  
Age Group ◽  
Background Population ◽  
Norwegian Population ◽  
Reference Limits ◽  
Laboratory Reference

AbstractLaboratory reference intervals are not necessarily reflecting the range in the background population. This study compared creatine kinase (CK) reference intervals calculated from a large sample from a Norwegian population with those elaborated by the Nordic Reference Interval Project (NORIP). It also assessed the pattern of CK-normalization after standardized control analyses.New upper reference limits (URL) CK values were calculated after exclusion of individuals with risk of hyperCKemia and including individuals with incidentally detected hyperCKemia after they had completed a standardized control analysis. After exclusion of 5924 individuals with possible causes of hyperCKemia, CK samples were analyzed in 6904 individuals participating in the 6th survey of The Tromsø Study. URL was defined as the 97.5 percentile.New URL in women was 207 U/L. In men <50 years it was 395 U/L and in men ≥50 years 340 U/L. In individuals with elevated CK, normalization grade after control analysis was inversely correlated to the CK level (p<0.04).URL CK values in women and in men <50 years of age were in accordance with URL CK values given by the NORIP. In men ≥50 years, a higher URL was found and the findings suggest an upward adjustment of URL in this age group.

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