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2.
Leukemia ; 33(8): 1910-1922, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30858550

RESUMO

Minimal residual disease (MRD) is a powerful prognostic factor in acute lymphoblastic leukemia (ALL) and is used for patient stratification and treatment decisions, but its precise role in Philadelphia chromosome positive ALL is less clear. This uncertainty results largely from methodological differences relating to the use of real-time quantitative PCR (qRT-PCR) to measure BCR-ABL1 transcript levels for MRD analysis. We here describe the first results by the EURO-MRD consortium on standardization of qRT-PCR for the e1a2 BCR-ABL1 transcript in Ph + ALL, designed to overcome the lack of standardisation of laboratory procedures and data interpretation. Standardised use of EAC primer/probe sets and of centrally prepared plasmid standards had the greatest impact on reducing interlaboratory variability. In QC1 the proportion of analyses with BCR-ABL1/ABL1 ratios within half a log difference were 40/67 (60%) and 52/67 (78%) at 10-3 and 36/67 (53%) and 53/67 (79%) at 10-4BCR-ABL1/ABL1. Standardized RNA extraction, cDNA synthesis and cycler platforms did not improve results further, whereas stringent application of technical criteria for assay quality and uniform criteria for data interpretation and reporting were essential. We provide detailed laboratory recommendations for the standardized MRD analysis in routine diagnostic settings and in multicenter clinical trials for Ph + ALL.


Assuntos
Proteínas de Fusão bcr-abl/genética , Cromossomo Filadélfia , Guias de Prática Clínica como Assunto , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Reação em Cadeia da Polimerase em Tempo Real/métodos , Consenso , Humanos , Neoplasia Residual , RNA Mensageiro/análise
3.
Leukemia ; 29(2): 369-76, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25036192

RESUMO

Serial quantification of BCR-ABL1 mRNA is an important therapeutic indicator in chronic myeloid leukaemia, but there is a substantial variation in results reported by different laboratories. To improve comparability, an internationally accepted plasmid certified reference material (CRM) was developed according to ISO Guide 34:2009. Fragments of BCR-ABL1 (e14a2 mRNA fusion), BCR and GUSB transcripts were amplified and cloned into pUC18 to yield plasmid pIRMM0099. Six different linearised plasmid solutions were produced with the following copy number concentrations, assigned by digital PCR, and expanded uncertainties: 1.08±0.13 × 10(6), 1.08±0.11 × 10(5), 1.03±0.10 × 10(4), 1.02±0.09 × 10(3), 1.04±0.10 × 10(2) and 10.0±1.5 copies/µl. The certification of the material for the number of specific DNA fragments per plasmid, copy number concentration of the plasmid solutions and the assessment of inter-unit heterogeneity and stability were performed according to ISO Guide 35:2006. Two suitability studies performed by 63 BCR-ABL1 testing laboratories demonstrated that this set of 6 plasmid CRMs can help to standardise a number of measured transcripts of e14a2 BCR-ABL1 and three control genes (ABL1, BCR and GUSB). The set of six plasmid CRMs is distributed worldwide by the Institute for Reference Materials and Measurements (Belgium) and its authorised distributors (https://ec.europa.eu/jrc/en/reference-materials/catalogue/; CRM code ERM-AD623a-f).


Assuntos
Proteínas de Fusão bcr-abl/genética , Proteínas de Fusão bcr-abl/metabolismo , Plasmídeos/genética , Reação em Cadeia da Polimerase em Tempo Real/normas , Calibragem , Clonagem Molecular , DNA , Proteínas de Escherichia coli/genética , Dosagem de Genes , Humanos , Proteínas de Membrana Transportadoras/genética , Proteínas Proto-Oncogênicas c-bcr/genética , RNA Mensageiro/metabolismo , Padrões de Referência
4.
Blood Cancer J ; 4: e250, 2014 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-25303369

RESUMO

Multiparameter flow cytometry (MFC) and allele-specific oligonucleotide real-time quantitative PCR (ASO RQ-PCR) are the two most sensitive methods to detect minimal residual disease (MRD) in multiple myeloma (MM). We compared these methods in 129 paired post-therapy samples from 22 unselected, consecutive MM patients in complete/near complete remission. Appropriate immunophenotypic and ASO RQ-PCR-MRD targets could be detected and MRD analyses constructed for all patients. The high PCR coverage could be achieved by gradual widening of the primer sets used for clonality detection. In addition, for 13 (55%) of the patients, reverse orientation of the ASO primer and individual design of the TaqMan probe improved the sensitivity and specificity of ASO RQ-PCR analysis. A significant nonlinear correlation prevailed between MFC-MRD and PCR-MRD when both were positive. Discordance between the methods was found in 32 (35%) paired samples, which were negative by MFC-MRD, but positive by ASO RQ-PCR. The findings suggest that with the described technique, ASO RQ-PCR can be constructed for all patients with MM. ASO RQ-PCR is slightly more sensitive in MRD detection than 6-10-color flow cytometry. Owing to technical demands ASO RQ-PCR could be reserved for patients in immunophenotypic remission, especially in efficacy comparisons between different drugs and treatment modalities.


Assuntos
Citometria de Fluxo/métodos , Mieloma Múltiplo/sangue , Reação em Cadeia da Polimerase em Tempo Real/métodos , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Neoplasia Residual
6.
Leukemia ; 25(7): 1168-73, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21494256

RESUMO

Quantitative PCR (qPCR) for detection of fusion transcripts and overexpressed genes is a promising tool for following minimal residual disease (MRD) in patients with hematological malignancies. Its widespread clinical use has to some extent been hampered by differences in data analysis and presentation that complicate multicenter clinical trials. To address these issues, we designed a highly flexible MRD-reporting software program, in which data from various qPCR platforms can be imported, processed, and presented in a uniform manner to generate intuitively understandable reports. The software was tested in a two-step quality control (QC) study; the first step involved eight centers, whose previous experience with the software ranged from none to extensive. The participants received cDNA from consecutive samples from a BCR-ABL+ chronic myeloid leukemia (CML) patient and an acute myeloid leukemia (AML) patient with both CBFß-MYH11 and WT1 target genes, they conducted qPCR on their respective hardware platforms and generated a series of reports with pre-defined features. In step two, five centers used the software to report BCR-ABL+ MRD in a harmonized manner, applying their recently obtained CML international scale conversion factors. The QC study demonstrated that this MRD-reporting software is suitable for efficient handling of qPCR data, generation of MRD reports and harmonization of MRD data.


Assuntos
Sistemas de Gerenciamento de Base de Dados , Bases de Dados Genéticas , Neoplasia Residual/genética , Relatório de Pesquisa/normas , Reação em Cadeia da Polimerase Via Transcriptase Reversa/estatística & dados numéricos , DNA Complementar/genética , DNA de Neoplasias/genética , Europa (Continente)/epidemiologia , Genes do Tumor de Wilms , Humanos , Serviços de Informação , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mieloide Aguda/genética , Neoplasia Residual/epidemiologia , Proteínas de Fusão Oncogênica/genética , Controle de Qualidade , Reprodutibilidade dos Testes , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Pesquisa Translacional Biomédica/métodos
7.
Leukemia ; 21(7): 1481-7, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17476280

RESUMO

Monitoring of BCR-ABL transcripts has become established practice in the management of chronic myeloid leukemia. However, nucleic acid amplification techniques are prone to variations which limit the reliability of real-time quantitative PCR (RQ-PCR) for clinical decision making, highlighting the need for standardization of assays and reporting of minimal residual disease (MRD) data. We evaluated a lyophilized preparation of a leukemic cell line (K562) as a potential quality control reagent. This was found to be relatively stable, yielding comparable respective levels of ABL, GUS and BCR-ABL transcripts as determined by RQ-PCR before and after accelerated degradation experiments as well as following 5 years storage at -20 degrees C. Vials of freeze-dried cells were sent at ambient temperature to 22 laboratories on four continents, with RQ-PCR analyses detecting BCR-ABL transcripts at levels comparable to those observed in primary patient samples. Our results suggest that freeze-dried cells can be used as quality control reagents with a range of analytical instrumentations and could enable the development of urgently needed international standards simulating clinically relevant levels of MRD.


Assuntos
Perfilação da Expressão Gênica/métodos , Perfilação da Expressão Gênica/normas , Reação em Cadeia da Polimerase/métodos , Proteínas Tirosina Quinases/genética , RNA Mensageiro/análise , Liofilização , Proteínas de Fusão bcr-abl , Humanos , Indicadores e Reagentes , Células K562 , Reação em Cadeia da Polimerase/normas , Proteínas Tirosina Quinases/análise , Controle de Qualidade , Padrões de Referência
8.
Neurology ; 67(5): 756-60, 2006 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-16966535

RESUMO

OBJECTIVE: To examine the association between hippocampal volumes, general brain atrophy, and apolipoprotein E (APOE) polymorphism in patients with a remote traumatic brain injury (TBI). METHODS: MRI-based volumetric analyses of the hippocampus and lateral ventricles were performed in 58 patients with TBI of varying severity on average 31.3 years after the trauma. The APOE genotype was determined using standard methods and correlated with the MRI volumetric measurements. RESULTS: Hippocampal or lateral ventricle volumes did not differ significantly in those patients with the APOE-epsilon4 allele (APOE4) vs those without this allele. CONCLUSIONS: The APOE-epsilon4 allele was not associated with the development of hippocampal or ventricular atrophy after traumatic brain injury. If the APOE-epsilon4 allele is associated with an unfavorable outcome after traumatic brain injury as proposed, this association may involve mechanisms other than those responsible for the development of brain atrophy.


Assuntos
Apolipoproteínas E/genética , Lesões Encefálicas/genética , Lesões Encefálicas/patologia , Hipocampo/patologia , Idoso , Análise de Variância , Apolipoproteína E4 , Atrofia , Demência/genética , Demência/patologia , Feminino , Genótipo , Humanos , Ventrículos Laterais/patologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/metabolismo , Estudos Retrospectivos , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Fatores de Tempo
9.
Acta Neurol Scand ; 111(3): 154-62, 2005 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15691283

RESUMO

OBJECTIVES: Frequency and distribution of dominant ataxias caused by dynamic mutations may vary in different populations, which has been explained on the basis of relative frequency of predisposing normal alleles. The aim of the study was to evaluate the occurrence of spinocerebellar ataxias (SCAs) and dentatorubral-pallidoluysian atrophy (DRPLA) in Finland, and to investigate the role of predisposing normal alleles in a genetically homogenous population. MATERIAL AND METHODS: Mutation analyses for SCA1, 2, 3, 6, 7, 8, 10, 12, 17, and DRPLA and frataxin genes were performed for 251 unrelated Finnish patients who presented with progressive ataxia disorder. RESULTS: Expansions of SCA1, SCA2, SCA6, SCA7, SCA8, and SCA17 genes were detected in 2, 1, 1, 7, 22, and 1 patients, respectively. Altogether, 39 and 7% of dominant and sporadic SCA patients, respectively, harboured expansions at some of the investigated loci. Normal variation, collected from 477 to 502 chromosomes at each disease loci, revealed that Finns were different from the Japanese but largely similar to other Caucasians. CONCLUSIONS: Lack of SCA3 and excess of SCA8 are characteristic to the Finnish population. Homozygosity for the SCA8 expansion increases penetrance. Frequencies of large normal alleles at the SCA loci predict poorly prevalence of the respective diseases in Finland. Prioritization in DNA testing, based on ethnic origin and geographical location, is recommendable in Finland, and analogous approach may be applied to other countries as well.


Assuntos
Ataxias Espinocerebelares/epidemiologia , Ataxias Espinocerebelares/genética , Ataxina-1 , Ataxina-3 , Ataxinas , Canais de Cálcio/genética , Expansão das Repetições de DNA , Finlândia/epidemiologia , Frequência do Gene , Humanos , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Penetrância , Proteínas/genética , Proteínas Repressoras
10.
Neurology ; 63(4): 749-50, 2004 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-15326261

RESUMO

The authors studied the association between APOE-epsilon4 genotype and axis I and II psychiatric disorders an average of 30 years after traumatic brain injury. Sixty patients were dichotomized into subjects with and without APOE-epsilon4 allele. Dementia and subclinical dementia were significantly more common with the presence of APOE-epsilon4. The occurrence of other psychiatric disorders did not differ between patients with and without APOE-epsilon4 allele.


Assuntos
Apolipoproteínas E/genética , Lesões Encefálicas/complicações , Demência/genética , Idoso , Alelos , Amnésia/epidemiologia , Amnésia/etiologia , Apolipoproteína E4 , Lesões Encefálicas/epidemiologia , Demência/epidemiologia , Demência/etiologia , Feminino , Finlândia/epidemiologia , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Transtornos Mentais/complicações , Transtornos Mentais/epidemiologia , Transtornos Mentais/genética , Pessoa de Meia-Idade , Testes Neuropsicológicos , Fatores de Risco , Fatores de Tempo
11.
Scand J Clin Lab Invest ; 64(4): 271-84, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15223694

RESUMO

Each of 102 Nordic routine clinical biochemistry laboratories collected blood samples from at least 25 healthy reference individuals evenly distributed for gender and age, and analysed 25 of the most commonly requested serum/plasma components from each reference individual. A reference material (control) consisting of a fresh frozen liquid pool of serum with values traceable to reference methods (used as the project "calibrator" for non-enzymes to correct reference values) was analysed together with other serum pool controls in the same series as the project samples. Analytical data, method data and data describing the reference individuals were submitted to a central database for evaluation and calculation of reference intervals intended for common use in the Nordic countries. In parallel to the main project, measurements of commonly requested haematology properties on EDTA samples were also carried out, mainly by laboratories in Finland and Sweden. Aliquots from reference samples were submitted to storage in a central bio-bank for future establishment of reference intervals for other properties. The 25 components were, in alphabetical order: alanine transaminase, albumin, alkaline phosphatase, amylase, amylase pancreatic, aspartate transaminase, bilirubins, calcium, carbamide, cholesterol, creatine kinase, creatininium, gamma-glutamyltransferase, glucose, HDL-cholesterol, iron, iron binding capacity, lactate dehydrogenase, magnesium, phosphate, potassium, protein, sodium, triglyceride and urate.


Assuntos
Biomarcadores/sangue , Química Clínica/normas , Testes de Química Clínica/normas , Medicina Clínica/normas , Laboratórios Hospitalares/normas , Valores de Referência , Europa (Continente) , Feminino , Humanos , Cooperação Internacional , Masculino
12.
Scand J Clin Lab Invest ; 64(4): 327-42, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15223699

RESUMO

The rules for recruitment of reference individuals, inclusion and preparation of individuals, blood collection, treatment of samples (and control materials) and analysis at the 102 medical laboratories attending the Nordic Reference Interval Project (NORIP) are given as well as the rules for central exclusion of reference individuals. The individuals (18-91-year-olds) should be evenly distributed on age and gender groups. The 3002 reference individuals who contributed at least one reference value to the finally suggested reference intervals were characterized using the information in the questionnaire. Gender, age and country are the main entries in the tables. Other variables in the cross-tables or figure are height, weight, body mass index, ethnic origin, heredity for diabetes, chronic disease, oestrogens or oral contraceptives, other medication, hard physical activity, previous blood donations, smoking habits, use of alcohol, hours since last meal and time of blood collection (hour, day of week, month, year). The Danes had the highest alcohol consumption and the Icelanders had the highest body mass index. The information in this article may interest potential users of the Nordic Reference Interval Project bio-bank and database (NOBIDA) in which serum, Li-heparin plasma and EDTA buffy coat from the mentioned individuals are stored below -80 degrees C.


Assuntos
Coleta de Amostras Sanguíneas/normas , Química Clínica/normas , Medicina Clínica/normas , Cooperação Internacional , Valores de Referência , Inquéritos e Questionários , Adolescente , Adulto , Idoso , Coleta de Amostras Sanguíneas/métodos , Europa (Continente) , Feminino , Humanos , Laboratórios Hospitalares/normas , Masculino , Pessoa de Meia-Idade
13.
Scand J Clin Lab Invest ; 64(4): 385-98, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15223702

RESUMO

Eight haematological quantities were measured in EDTA anticoagulated venous blood specimens collected from 1826 healthy male and female individuals between 18 and 90 years of age in the Nordic countries (Denmark, Finland, Iceland, Norway and Sweden). The samples, collected between November 1999 and November 2001 as part of the Nordic Reference Interval Project (NORIP), were analysed on 12 different types of modern automated haematology instruments currently in use among the 60 laboratories participating in the study. Non-parametric reference intervals (between 2.5 and 97.5 percentiles) have been calculated for B-Haemoglobin (females 117-153 g/L, males 134-170 g/L), B-Erythrocytes (females 3.94-5.16 x 10(12)/L, males 4.25-5.71 x 10(12)/L), B-EVF (females 0.348-0.459, males 0.395-0.500), B-MCV (82-98 fL), Erc-MCH (27.1-33.3 pg), Erc-MCHC (317-357 g/L), B-Trc (females 165-387 x 10(9)/L, males 145 x 348 x 10(9)/L) and B-Lkc (3.5-8.8 x 10(9)/L). Partitioning of data according to age and gender was done according to a standardized procedure. For most variables the calculated reference intervals corresponded well with older and less well-defined reference intervals. The mean concentration of B-Haemoglobin increased by 0.08 g/L per year of age in women, and decreased by 0.1 g/L per year of age in men. B-Haemoglobin increased with body mass index in both men and women. Smoking increased the mean of B-Lkc by 1.1 x 10(9)/L and regular use of alcohol increased the mean of B-MCV by 0.8 fL. The influence of these factors was small overall and did not promote specific reference intervals.


Assuntos
Química Clínica/normas , Medicina Clínica/normas , Testes Hematológicos/normas , Cooperação Internacional , Valores de Referência , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Europa (Continente) , Feminino , Testes Hematológicos/métodos , Humanos , Laboratórios Hospitalares/normas , Masculino , Pessoa de Meia-Idade
15.
Clin Chem ; 46(10): 1540-7, 2000 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11017930

RESUMO

BACKGROUND: An accurate determination of the major HFE mutation (C282Y), which is associated with hereditary hemochromatosis, is important in diagnosis and risk assessment for this disease. We report a single-tube high-throughput PCR method for the detection of C282Y. METHODS: We combined three previously described principles: allele-specific PCR, mutagenically separated PCR, and amplicon identification by specific dissociation curves. PCR amplification was performed with fluorescence detection or conventional thermocycler using the same primers, reactant constituents, and cycling protocol. Primer cross-reactions were prevented by deliberate primer:primer and primer:template mismatches. RESULTS: PCR products were identified by their characteristic melting temperatures based on SYBR Green I fluorescence. For each of the 256 random and 17 known HFE C282Y samples, mutant homozygous, wild-type, and heterozygous samples were unequivocally distinguished. CONCLUSIONS: This homogeneous assay is rapid, reproducible, does not require fluorescent oligonucleotide probes, and correctly identifies HFE genotypes.


Assuntos
Antígenos HLA/genética , Hemocromatose/genética , Antígenos de Histocompatibilidade Classe I/genética , Proteínas de Membrana , Alelos , Substituição de Aminoácidos , Genótipo , Proteína da Hemocromatose , Humanos , Mutação , Reação em Cadeia da Polimerase/métodos , Reprodutibilidade dos Testes
18.
Clin Chem ; 44(11): 2353-8, 1998 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-9799764

RESUMO

Regression analysis is the method of choice for the production of covariate-dependent reference limits. There are currently no recommendations on what sample size should be used when regression-based reference limits and confidence intervals are calculated. In this study we used Monte Carlo simulation to study a reference sample group of 374 age-dependent hemoglobin values. From this sample, 5000 random subsamples, with replacement, were constructed with 10-220 observations per sample. Regression analysis was used to estimate age-dependent 95% reference intervals for hemoglobin concentrations and erythrocyte counts. The maximum difference between mean values of the root mean square error and original values for hemoglobin was 0.05 g/L when the sample size was > or = 60. The parameter estimators and width of reference intervals changed negligibly from the values calculated from the original sample regardless of what sample size was used. SDs and CVs for these factors changed rapidly up to a sample size of 30; after that changes were smaller. The largest and smallest absolute differences in root mean square error and width of reference interval between sample values and values calculated from the original sample were also evaluated. As expected, differences were largest in small sample sizes, and as sample size increased differences decreased. To obtain appropriate reference limits and confidence intervals, we propose the following scheme: (a) check whether the assumptions of regression analysis can be fulfilled with/without transformation of data; (b) check that the value of v, which describes how the covariate value is situated in relation to both the mean value and the spread of the covariate values, does not exceed 0.1 at minimum and maximum covariate positions; and (c) if steps 1 and 2 can be accepted, the reference limits with confidence intervals can be produced by regression analysis, and the minimum acceptable sample size will be approximately 70.


Assuntos
Hemoglobinas/normas , Pré-Escolar , Intervalos de Confiança , Contagem de Eritrócitos/métodos , Humanos , Lactente , Método de Monte Carlo , Valores de Referência , Análise de Regressão , Tamanho da Amostra
19.
Clin Chem Lab Med ; 36(7): 485-91, 1998 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-9746274

RESUMO

Information on biological day-to-day variation is needed for detecting within-subject changes over time. In this study the daytime changes and the biological day-to-day variation of serum testosterone, follitropin, lutropin and oestradiol-17beta concentrations were investigated in 31 healthy males. To analyse daytime changes, blood specimens were taken at 0800 h, 1200 h, 1600 h and 2000 h during one day (n=31) and two days (n=8). The day-to-day variation was analysed from blood specimens collected at 0800 h on days 1 and 2 (n=31) and additionally on days 3, 4, 6 and 9 (n=8). The evaluation of the day-to-day variation was based on calculations of the within-subject (CVA+I) and between-subject (CV(G)) coefficients of variation. When the within-subject day-to-day variances were not too heterogeneous, they were used for the calculation of 95 % reference change limits. Serum testosterone and oestradiol-17beta concentrations showed a significant daytime variation; testosterone had higher serum concentrations at 0800 and 1200 h. A peak in the serum concentration of oestradiol-17beta occurred at 1200 h with a decrease towards the evening. There were no clear daytime changes in the serum concentrations of follitropin or lutropin. For different analytes the reference change limits were: serum testosterone +/- 32.0 %, serum follitropin +/- 24.1 % and serum oestradiol-17beta +/- 38.3 %. The reference change limit was not calculated for serum lutropin, as a high degree of heterogeneity and individuality was found. The interpretation of the results of hormone measurements requires recognition of the biological daytime and day-to-day changes of hormones. The reference change limits determine what changes are significant when monitoring the patient.


Assuntos
Ritmo Circadiano/fisiologia , Estradiol/sangue , Hormônio Foliculoestimulante/sangue , Hormônio Luteinizante/sangue , Testosterona/sangue , Adulto , Análise de Variância , Humanos , Masculino
20.
Clin Chem ; 44(2): 327-35, 1998 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-9474032

RESUMO

Calculation of reference limits by regression analysis makes it unnecessary to partition the reference data into subgroups, and age-dependent limits can be estimated within as narrow age intervals as necessary. However, the reliability of the regression-based reference limits has not been considered before. To get valid regression-based confidence intervals (CIs) for reference limits, one must evaluate the convolution of two distributions. In this study, age-dependent reference limits with corresponding CIs were produced for blood hemoglobin concentrations over the age interval from newborns to 12 months. We describe how the variance associated with the reference limits can be estimated, and present a Table from which appropriate values can be chosen for the calculation of regression-based reference limits and exact CIs. Also, an equation for the calculation of approximate CIs is given. The data were modeled by linear regression in several cumulative age groups to find the transition zone where the slope changed. After defining this cutoff point, piecewise linear regression was applied. Reference limits and their CIs calculated by conventional and piecewise linear regression methods were almost the same in older age groups but differed significantly during the period of most rapid age-dependent changes, i.e., during the 2 months after birth.


Assuntos
Hemoglobinas/análise , Fatores Etários , Intervalos de Confiança , Finlândia , Humanos , Lactente , Recém-Nascido , Padrões de Referência , Análise de Regressão
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