Revisión del intervalo de referencia del recuento plaquetario: ¿son adecuados los valores que estamos utilizando? / Review of the platelet count reference range: are the values we are using appropriate?

Los intervalos de referencia (IR) dependen de la población y de las características metrológicas del procedimiento de medida utilizado. A pesar de las recomendaciones internacionales, son pocos los laboratorios que establecen sus propios IR para cada magnitud por la dificultad para conseguir voluntarios de referencia y el elevado costo económico asociado. La International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) acepta la adopción de IR bibliográficos o su cálculo por métodos indirectos dado su bajo costo y fácil obtención. Existen varias fuentes confiables de IR bibliográficos para el hemograma. No obstante, para el recuento plaquetario, es una práctica común de los laboratorios emplear el rango de valores de 150-450.109 /L independiente de la metodología utilizada y grupo etario. El objetivo de este trabajo fue revisar los IR bibliográficos disponibles para el recuento plaquetario y estimarlo empleando el método indirecto de Hoffmann a partir de nuestra población. Los métodos indirectos se basan en aplicar criterios de exclusión y cálculos matemáticos sobre los resultados de una base de datos de laboratorio. Nuestros IR para el recuento plaquetario se comparan con los bibliográficos, que han sido establecidos por técnicas de muestreo directo. Por este motivo y dado que no existen estudios poblacionales que lo avalen, sería apropiado reemplazar el rango de 150-450.109 / L. Estos límites podrían seguir empleándose como puntos de corte o niveles de decisión médica para definir, según la clínica y otros resultados de laboratorio, los pacientes que ameritan un seguimiento posterior (AU)

Reference ranges (RR) depend on the population and the metrological characteristics of the measurement procedure used. Despite international recommendations, few laboratories establish their own RRs for each magnitude because of the difficulty in obtaining reference volunteers and the associated high economic cost. The International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) accepts the use of literaturebased RRs or RRs calculated by indirect methods because of their low cost and easy collection. There are several reliable sources of literature-based RRs for the Cell Blood Count. However, for platelet count, it is common laboratory practice to use the range of 150-450,109 /L regardless of the methodology used and age group. The aim of this study was to review the available literature regarding RRs for platelet count and to establish it using the indirect Hoffmann method in our population. Indirect methods are based on applying exclusion criteria and mathematical calculations on the results of a laboratory database. Our RRs for platelet counts are compared with those in the literature, which have been established by direct sampling techniques. Therefore, and given that there are no population studies to support these findings, it would be appropriate to replace the 150-450,109 /L range. These limits may continue to be used as cut-off points or medical decision levels to define, according to clinical manifestations and other laboratory results, patients who warrant further follow-up (AU)

Intervalos de referencia en pediatría. Una guía de sus formas de cálculo ordenadas según su fortaleza metodológica / Pediatrics reference intervals. A guide of its calculation forms ordered according to their methodological strength

Resumen El objetivo de esta comunicación es proponer una guía de las formas decálculo de los intervalos de referencia (IR) en la población pediátrica ordenándolassegún su fortaleza metodológica. En primer lugar, el proceso recomendadopara definir un IR es el enfoque "directo", en el que se evalúanmuestras de sujetos considerados sanos. En segundo lugar, la convocatoria"indirecta", en la que a los resultados de las muestras de una base dedatos, se aplican criterios de exclusión y procesamientos estadísticos (métodosde Hoffmann y de Bhattacharya). Estos IR presentan poca diferenciacon los obtenidos por datos directos y se pueden considerar equivalentes,con la ventaja de su facilidad y sus costos más bajos. En tercer lugar, estánlos IR obtenidos de la bibliografía. La validación de los datos informadospor el fabricante es la última opción a tener en cuenta. Se reafirma laimportancia de contar con IR adecuados por sus aspectos clínicos y por laseguridad de los pacientes.

Abstract The aim of this communication is to propose a guide on the ways of calculating reference intervals (RI) in the pediatric population, ordering them according to their methodological strength. First, the recommended process to define an RI is the "direct" approach, in which samples of subjects considered healthy are evaluated. Secondly, the "indirect" approach, in which exclusion criteria and statistical processing are applied to the results ofthe samples in a database (Hoffmann and Bhattacharya methods). These RIs show little differences with those obtained by direct data and they can be considered equivalent, with the advantage of their ease and with lower costs. Thirdly, there are RIs that can be obtained from the bibliography. The validation of the data reported by the manufacturer is the last option to consider. The importance of having adequate RIs for their clinical aspects and for the safety of patients is reaffirmed.

Resumo O objetivo desta comunicação é propor um guia sobre as formas de cálculo dos intervalos de referência (IR) na população pediátrica, ordenando os mesmos de acordo com sua fortaleza metodológica. Emprimeiro lugar, o processo recomendado para definir um IR é a abordagem "direta", na qual sãoavaliadas amostras de indivíduos considerados saudáveis. Em segundo lugar, a abordagem "indireta",na qual critérios de exclusão e processamento estatístico (métodos de Hoffmann e Bhattacharya)são aplicados aos resultados das amostras em um banco de dados. Esses IR apresentam poucadiferença com os obtidos por dados diretos, podendo ser considerados equivalentes, com a vantagem de apresentarem facilidade e menor custo. Em terceiro lugar, os IR obtidos da bibliografia. A validadedos dados informados pelo fabricante é a última opção a ser considerada. A importância de termos IRadequados pelos seus aspectos clínicos e pela segurança dos pacientes é reafirmada.

Comparison of reference intervals derived by direct and indirect methods based on compatible datasets obtained in Turkey.

BACKGROUND: Indirect derivation of reference intervals (RIs) from the laboratory information system (LIS) has been recently pursued. We aimed at evaluating the accuracy of indirectly predicted RIs compared to the RIs established directly from healthy subjects in the nationwide RI study in Turkey, targeting 25 major chemistry analytes. METHODS: LIS data were retrieved from the laboratory that performed measurements for the direct study. They were cleaned by limiting to outpatients with age 18-65 years, and by allowing only one record per year per patient. Evaluated were four indirect methods of univariate approach: Hoffmann, Bhattacharya, Arzideh, and Wosniok methods. Power transformation of the LIS dataset was performed either using the power (λ) reported by the IFCC global RI study (the first two methods) or using a λ predicted (the last two). RESULTS: Compared to the direct study dataset, the LIS dataset showed a variable degree of alterations in peak location and shape. Consequently, lower-side peak-shifts observed in sodium, albumin, etc. led to lowered RI limits, whereas higher-side peak-shift observed in triglyceride, low-density lipoprotein cholesterol, etc. led to raised RI limits. Overall, 72% (62-81) of the RI limits predicted by indirect methods showed significant biases from direct RIs. However, the biases observed in total cholesterol, lactic dehydrogenase, etc. were attributed to a higher-side age-bias in LIS dataset. After excluding them, the overall proportion of biased RIs was reduced to 47% (38-54). CONCLUSION: To reduce prediction biases that remained after age adjustment, it is necessary to apply more rigorous data-cleaning before applying indirect methods.

Verifying Clinically Derived Reference Intervals for Daily Excretion Rates of Fractionated Metanephrines Using Modern Indirect Reference Interval Models.

OBJECTIVES: Biochemical testing of urinary metanephrines is useful in the diagnosis and monitoring of pheochromocytoma and paragangliomas. We investigated the feasibility of mixture decomposition (ie, indirect) methods in verifying clinically derived reference intervals for urinary deconjugated metanephrine metabolites. METHODS: Urinary 24-hour metanephrine and normetanephrine excretion results were extracted from our data warehouse and intervals were estimated by the modern variant of the Hoffmann method, maximum likelihood estimation (MLE), and gamma mixture model using R software. RESULTS: Hoffmann, MLE, and gamma mixture models provided metanephrine and normetanephrine intervals that closely matched those derived from clinical studies. However, three-component MLE and gamma models were required for normetanephrine in adult women because the Hoffmann method was not suitable. Some data transformations caused blending of the mixed distributions and subsequent widening of the reference interval estimation, emphasizing the importance of careful data transformation for Hoffmann and MLE analyses. Gamma mixture models gave overall good agreement without the need for data transformation. CONCLUSIONS: Indirect methods have utility in verifying reference intervals in 24-hour urine specimens collected by patients. We emphasize the benefits of applying multiple decomposition methods to corroborate findings and careful application of data transformation when using Gaussian-based models.

Retinol and α-tocopherol in pregnancy: Establishment of reference intervals and associations with CBC.

Profound physiological changes during pregnancy may affect the requirement of retinol and tocopherol, which are essential micronutrients for the maintenance of maternal health and foetal development. However, the current reference intervals (RIs) of retinol and tocopherol are based on non-pregnant population. In the present study, a liquid chromatography-tandem mass spectrometry quantitation method for serum retinol and α-tocopherol was established and validated. In addition, we established trimester-specific RIs of retinol and α-tocopherol using the data from paired screening test for 31,301 outpatients who participated in the prenatal vitamins A/E evaluation program at our hospital using the Hoffmann method, which is a simple indirect RI estimation method that does not require the recruitment of healthy subjects. Further, to explore the associations between the levels of retinol and α-tocopherol and the parameters of complete blood count (CBC), the results of retinol, α-tocopherol, and CBC of 1,977 pregnant outpatients in the third trimester were analysed. The testing interval between the levels of vitamins and CBC was no more than 7 days. Although no significant changes were noticed in the levels of retinol, the α-tocopherol levels continuously increased with normal physiological changes throughout pregnancy. Lower retinol levels were associated with the higher incidence of anaemia, whereas higher levels of retinol and lower levels of α-tocopherol were associated with higher platelet count.

Limitations of the Hoffmann method for establishing reference intervals using clinical laboratory data.

OBJECTIVE: To examine the effect of different limits of acceptability on the Hoffmann method for selecting "healthy" populations from laboratory test data. METHODS: Thyroid stimulating hormone (TSH) and free thyroxine (FT4) were measured in Shunyi Maternal and Children's Hospital of Beijing Children's Hospital. The sample size of participants of TSH and FT4 for reference intervals (RIs) establishment was 10,864 and 10,799, respectively. RIs were calculated by Hoffmann method with different acceptable deviations (α value). The validation data was collected prospectively and the out-of-range (OOR) values were calculated to examine the applicability of RIs with different acceptable deviations. The sample size for RIs validation was 880 and 867, respectively. The RIs were considered as valid when OOR was <10%. RESULTS: α value was set at different levels for establishing the RIs of TSH and FT4. It was shown that the larger α value, the wider the RI. The RIs calculated by the Hoffmann method, under the default α value of 0.05, were much narrower than the previous findings. The OOR of both TSH and FT4 were far more from 10% when the α value was 0.05. In this simulation, the OOR of TSH and FT4 was not <10% until the α value was set as 0.55 and 0.80, respectively. The established RIs were valid for both training dataset and validation dataset. CONCLUSIONS: It can be somewhat subjective to define the acceptable deviation when selecting "normal" reference individuals. The default value of acceptable deviation may not be applicable in some cases. It is necessary to determine the acceptable deviation based on the certain condition, instead of using the default value directly.