Reference values for serum folate and vitamin B12 in a Spanish population using an electrochemiluminiscent method

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Controlled provocation and new markers" ] ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "José Antonio Garrote, Ángel San Miguel, Jesús Pachón, Rosario Pastor, Emilio Rodríguez Barbero" "autores" => array:5 [ 0 => array:2 [ "nombre" => "José Antonio" "apellidos" => "Garrote" ] 1 => array:2 [ "nombre" => "Ángel" "apellidos" => "San Miguel" ] 2 => array:2 [ "nombre" => "Jesús" "apellidos" => "Pachón" ] 3 => array:2 [ "nombre" => "Rosario" "apellidos" => "Pastor" ] 4 => array:2 [ "nombre" => "Emilio" "apellidos" => "Rodríguez Barbero" ] ] ] ] ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1888400817301162?idApp=UINPBA00004N" "url" => "/18884008/0000001100000003/v1_201807060854/S1888400817301162/v1_201807060854/es/main.assets" ] "en" => array:19 [ "idiomaDefecto" => true "cabecera" => "Original article" "titulo" => "Reference values for serum folate and vitamin B12 in a Spanish population using an electrochemiluminiscent method" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "118" "paginaFinal" => "122" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "José Luis Martín Calderón, Luis Caballero, Fernando Solano, Fernando Bustos" "autores" => array:4 [ 0 => array:4 [ "nombre" => "José Luis" "apellidos" => "Martín Calderón" "email" => array:1 [ 0 => "jlmartinc@sescam.jccm.es" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Luis" "apellidos" => "Caballero" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 2 => array:3 [ "nombre" => "Fernando" "apellidos" => "Solano" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 3 => array:3 [ "nombre" => "Fernando" "apellidos" => "Bustos" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Department of Clinical Chemistry, Hospital Nuestra Señora del Prado, Talavera de la Reina, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Department of Haematology, Hospital Nuestra Señora del Prado, Talavera de la Reina, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Valores de referencia de ácido fólico y vitamina B12 séricos en una población española, utilizando un método de electroquimioluminiscencia" ] ] "textoCompleto" => "IntroductionFolate and vitamin B12 are water soluble vitamins involved in one carbon transfer (methylation) reactions necessary for the production of monoamine neurotransmitters, phospholipids and the nucleotides used in DNA synthesis.<a class="elsevierStyleCrossRefs" href="#bib0110">1–5</a> Vitamin B12 or folate depletion both increase homocysteine levels, being high circulating levels of homocysteine often consequence of an inadequate status of these vitamins.<a class="elsevierStyleCrossRef" href="#bib0135">6</a> Hyperhomocysteinaemia has been associated with cardiovascular, haematological and neurological diseases.<a class="elsevierStyleCrossRefs" href="#bib0135">6,7</a>Deficiency of folate or of cobalamin may cause different types of disorders, mainly haematological disorders<a class="elsevierStyleCrossRef" href="#bib0140">7</a> such as anaemia and macrocytosis, but also others as memory disturbances, delirium, mood disorders and psychoses.<a class="elsevierStyleCrossRefs" href="#bib0145">8,9</a> Folate and vitamin B12 deficiencies are still important problems worldwide. The difficulty to establish consensus levels is due to the fact that serum concentrations of these vitamins differ according to age, gender and other variables.<a class="elsevierStyleCrossRef" href="#bib0135">6</a> Vitamin B12 levels decrease with age, being clinical and subclinical deficiency more prevalent in the elderly.<a class="elsevierStyleCrossRef" href="#bib0155">10</a> Epidemiological data suggest an estimated prevalence of at least 10% of individuals over 60 years.<a class="elsevierStyleCrossRefs" href="#bib0130">5,11</a> Age influence is not so clear-cut in the case of folate levels.<a class="elsevierStyleCrossRef" href="#bib0165">12</a> In addition diet, habits, and physiological and pathological factors influence cobalamin and folate status. For instance, low vitamin B12 levels are more frequent in vegetarians,<a class="elsevierStyleCrossRefs" href="#bib0155">10,13</a> in patients with gastrointestinal diseases,<a class="elsevierStyleCrossRef" href="#bib0175">14</a> and in individuals with high alcohol consumption or with renal failure.<a class="elsevierStyleCrossRefs" href="#bib0155">10,14</a> Folate status is also negatively influenced by dietary, pathological (alcoholism, depression) and pharmacological (anticonvulsants) factors.<a class="elsevierStyleCrossRef" href="#bib0180">15</a> Variability is further enhanced by the compulsory fortification of flour with folate and vitamin B12 dictated by some government agencies.<a class="elsevierStyleCrossRefs" href="#bib0130">5,15</a> As a consequence, prevalence rates for folate and vitamin B12 deficiencies vary considerably across different studies.<a class="elsevierStyleCrossRef" href="#bib0165">12</a> Besides the aforementioned factors that promote variability, it is important to take also into account methodological differences, especially when immunoassays are used.The aim of this work is to define the reference values for serum folate and vitamin B12 in our population. According to Horn and Pesce,<a class="elsevierStyleCrossRef" href="#bib0185">16</a> reference intervals are the most widely used medical decision-making tools. Ideally, all clinical laboratories should determine their own reference values. However, most of them do not, due to the fact that the establishment of reliable reference intervals is a highly demanding activity,<a class="elsevierStyleCrossRef" href="#bib0190">17</a> and therefore the usual practice is to adopt the intervals provided in the manufacturer's inserts. We have calculated reference intervals for a population from Central Spain using an electrochemiluminiscent method (Roche Diagnostics) in a Modular E-170 analyzer.Materials and methodsPatientsOne hundred and forty one healthy volunteers aged 18–65 years were selected among blood donors of our hospital. Written informed consent was obtained from all of them. Abuse drug consumers, smokers and alcohol drinkers were excluded from the study. The individuals did not have noticeable previous disease, and were not being treated with prescription medications or vitamin supplements at the moment of inclusion. <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> shows the exclusion criteria used for patient selection. Blood was collected in serum separator tubes and serum samples obtained after centrifugation at 1000×g during 10min.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Biochemical analysisVitamin B12 and folate levels were measured using a competitive electrochemiluminiscent immunoassay in a Modular E170 analyzer (ROCHE DIAGNOSTICS®, Manheim, Germany). In this method the sample is first pretreated to release vitamin B12 and folate from their carrier proteins. The sample is then incubated with a ruthenium-labelled protein (intrinsic factor in the vitamin B12 assay and folate binding protein in the folate assay), giving rise to an analyte-protein complex whose concentration depends on the concentration of analyte in the sample. Subsequently, streptavidin-covered microparticles and biotin-labelled analyte are added. The latter occupies the remaining free binding sites on the ruthenium-labelled protein, and the resulting complex binds to the solid phase due to the interaction between biotin and streptavidin. The microparticles attach then to the surface of an electrode due to magnetic forces, non-bound components are washed away and, finally, an electric current is applied, which induces a chemiluminiscent reaction whose intensity is proportional to vitamin B12 or folate concentration.Statistical analysisData analysis was performed using the software package Medcalc 11.3 (Ostend, Belgium). Reference intervals were calculated using the non-parametric percentile method, following the recommendations of the Clinical Laboratory Standards Institute document CLSI C28 A3.<a class="elsevierStyleCrossRef" href="#bib0195">18</a> The presence of outliers was assessed using the Dixon's test.<a class="elsevierStyleCrossRef" href="#bib0185">16</a> Kolmogorov–Smirnov's test was used to evaluate the Gaussian distribution.Additionally, we examined if it was possible to partition reference values according to sex or age. The sample was split in three age categories: (I) 18–34 years; (II) 25–49 years and (III) 50–65 years. Assessment of differences between these groups was done using the Harris and Boyd criterion,<a class="elsevierStyleCrossRef" href="#bib0200">19</a> according to which separate intervals must be established if the ratio between the subgroup standard deviations is greater than 1.5.ResultsThe sample representing our population was composed of 141 healthy volunteers aged 18–65 years, 87 of them male (61.7%) and 54 female (38.3%). The age arithmetic mean was 41.9 years (median 43, standard deviation 12.1). The descriptive characteristics of the study group are shown on <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia><a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a> shows the results when the sample was split in age groups.<elsevierMultimedia ident="tbl0015"></elsevierMultimedia>Kolmogorov–Smirnov's test showed a Gaussian distribution for vitamin B12 but not for folate levels (<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>). The reference interval for folate ranged from 2.2 to 18ng/mL (5–40.7nmol/L), and in the case of vitamin B12 from 213.8 to 763.3pg/mL (158.2–564.8pmol/L). These reference intervals are shown on <a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>, where the numbers in brackets represent the 90% confidence intervals.<elsevierMultimedia ident="tbl0020"></elsevierMultimedia>Application of the Harris and Boyd's method leads us to conclude that there are no significant differences for folate or vitamin B12 concentration among different sex or age groups, as standard deviation ratios are under 1.5 in every case. Given that folate values did not show a Gaussian distribution logarithmic normal transformation was carried out for this variable before applying the Harris and Boyd's approximation.Reference intervals claimed by the manufacturer are shown in <a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a>.<elsevierMultimedia ident="tbl0025"></elsevierMultimedia>DiscussionOne of the critical aspects of the practice of clinical laboratory medicine is the assessment of test results to determine whether patients are healthy or, on the contrary, subject to some pathological condition. Thus, the inclusion of reference intervals in clinical laboratory reports is mandatory.<a class="elsevierStyleCrossRef" href="#bib0190">17</a> Each laboratory should produce its own reference values and estimate the corresponding reference intervals.<a class="elsevierStyleCrossRefs" href="#bib0205">20,21</a> However, this recommendation seems to have had limited impact in most clinical laboratories,<a class="elsevierStyleCrossRef" href="#bib0190">17</a> the usual practice being to adopt values included in the reagent inserts. This is due to the fact that the calculation of an adequate reference interval is a highly demanding and difficult activity.<a class="elsevierStyleCrossRefs" href="#bib0185">16,17</a> The Clinical Laboratory Standard Institute (CLSI) and the International Federation of Clinical Chemistry (IFCC) recommend the inclusion of at least 120 individuals in the calculation of a reference interval<a class="elsevierStyleCrossRefs" href="#bib0185">16,18,20</a>; this recommendation is widely fulfilled in our sample (n=141). Establishing reference intervals has always been a challenging task, as significant differences may exist between ethnic, gender or age groups, and as they may also vary depending on specimen collection techniques, test assays, and other factors. This variability is even greater in the cases of folate and vitamin B12 which, apart from the aforementioned factors, can also be influenced by diet, drug therapies, and policies of grain fortification. This reinforces the need of elaborating reference intervals for this analytes by every individual clinical laboratory.In our case, the manufacturer's change of the composition of folate and vitamin B12 reagents<a class="elsevierStyleCrossRef" href="#bib0210">21</a> (folate III, vitamin B12 II) has led to lower results than the ones we used to obtain with previous versions (particularly for folate). In spite of this fact, the reference intervals stated in the vendor's insert are similar to the previous ones. This has prompted us to produce our own reference values.As we expected, in the case of folate we obtained a 2.5 percentile considerably lower than the one claimed by the vendor (2.2 vs. 4.6ng/mL, or 5 vs. 10.2nmol/L), although upper limits were similar. The difference was not so marked in the case of vitamin B12, but our 2.5 percentile was also lower than that claimed by the manufacturer (197 vs. 213.8pg/mL, or 145.8 vs. 158.2pmol/L). This fact reinforces the need of each clinical laboratory to build its own reference intervals. When we applied Harris and Boyd method<a class="elsevierStyleCrossRef" href="#bib0200">19</a> to our data we found no age- or sex-related differences between serum vitamin levels. Although the influence of age in vitamin B12 status is well known,<a class="elsevierStyleCrossRefs" href="#bib0155">10–13</a> our sample did not include elderly people, a fact that explains the lack of difference between subclasses. Sex differences are not so clear cut in previously published studies,<a class="elsevierStyleCrossRefs" href="#bib0135">6,12</a> and accordingly we found no relation between reference intervals and sex.A limitation of our study is that we did not measure other metabolites such as homocysteine, methyl malonic acid or red blood content of folate. Although this would have exceeded the scope of our study, it would have been interesting in order to define more precisely the cobalamin and folate status in our population. Unfortunately, we have no available methods for the routine determination of these analytes in our laboratory.Ethical disclosuresProtection of human and animal subjectsThe authors declare that no experiments were performed on humans or animals for this study.Confidentiality of dataThe authors declare that no patient data appear in this article.Right to privacy and informed consentPatient data are not shown in this article.Conflict of interestThe Authors declare that they do not have any conflict of interest with the company which provides reagents and instrumentations." "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:3 [ "identificador" => "xres1052737" "titulo" => "Abstract" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Objective" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Method" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Results" ] 4 => array:2 [ "identificador" => "abst0025" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1003380" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1052736" "titulo" => "Resumen" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0030" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0035" "titulo" => "Objetivo" ] 2 => array:2 [ "identificador" => "abst0040" "titulo" => "Método" ] 3 => array:2 [ "identificador" => "abst0045" "titulo" => "Resultados" ] 4 => array:2 [ "identificador" => "abst0050" "titulo" => "Conclusiones" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1003381" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Materials and methods" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Patients" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Biochemical analysis" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Statistical analysis" ] ] ] 6 => array:2 [ "identificador" => "sec0030" "titulo" => "Results" ] 7 => array:2 [ "identificador" => "sec0035" "titulo" => "Discussion" ] 8 => array:3 [ "identificador" => "sec0040" "titulo" => "Ethical disclosures" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0045" "titulo" => "Protection of human and animal subjects" ] 1 => array:2 [ "identificador" => "sec0050" "titulo" => "Confidentiality of data" ] 2 => array:2 [ "identificador" => "sec0055" "titulo" => "Right to privacy and informed consent" ] ] ] 9 => array:2 [ "identificador" => "sec0060" "titulo" => "Conflict of interest" ] 10 => array:2 [ "identificador" => "xack355695" "titulo" => "Acknowledgments" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2017-08-09" "fechaAceptado" => "2017-11-02" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1003380" "palabras" => array:5 [ 0 => "Folate" 1 => "Vitamin B12" 2 => "Cobalamin" 3 => "Reference values" 4 => "Electrochemiluminescence" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1003381" "palabras" => array:5 [ 0 => "Folato" 1 => "Vitamina B12" 2 => "Cobalamina" 3 => "Valores de referencia" 4 => "Electroquimioluminiscencia" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "BackgroundDespite being the most widely used medical decision-making tool, reference intervals are not usually determined by clinical laboratories, due to the highly demanding activities and costly process it involves. However, scientific societies encourage individual clinical laboratories to establish their own reference values. This is especially important in the cases of folate and vitamin B12, due to strong differences in vitamin status among different populations. ObjectiveOur aim is to establish reference intervals for folate and vitamin B12 levels in a healthy blood donor population using an electrochemiluminiscent method (ROCHE DIAGNOSTICS). MethodFolate and vitamin B12 levels were measured in 141 healthy blood donors aged between 18 and 65 years. Biochemical analyses were performed using a Modular E170 analyzer (ROCHE DIAGNOSTICS) and an electrochemiluminiscent method. Reference intervals were calculated with a non-parametric percentile method following the CLSI guidelines. ResultsThere were not significant differences in folate or cobalamin levels between age or sex subgroups. The limits of the reference interval for folate were 2.2 and 18ng/mL (5–40.7nmol/L), and 213.8 and 763.3pg/mL (158.2–564.8pmol/L) for vitamin B12. These intervals differed from those claimed by the manufacturer. ConclusionsOur results emphasize the convenience of building reference values based on the population served by the laboratory, in order to unequivocally rule out deficiencies of folate or vitamin B12." "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Objective" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Method" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Results" ] 4 => array:2 [ "identificador" => "abst0025" "titulo" => "Conclusions" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "IntroducciónA pesar de ser una de las herramientas más usadas en la toma de decisiones médicas, los intervalos de referencia son raramente determinados en los laboratorios, debido a que es una labor compleja en términos de tiempo, esfuerzo y coste. Sin embargo las sociedades científicas recomiendan que los laboratorios establezcan sus propios valores de referencia. Esto es especialmente importante para el folato y la vitamina B12, debido a las grandes diferencias entre poblaciones. ObjetivoNuestro propósito es establecer los valores de referencia en una población de donantes sanos, mediante un método electroquimioluminiscente (Roche Diagnostics). MétodoLos niveles de folato y vitamina B12 se midieron en una muestra integrada por 141 donantes sanos de una edad comprendida entre 18 y 65 años. Los análisis bioquímicos se realizaron en un analizador Modular E170 (Roche Diagnostics). Los intervalos de referencia se calcularon siguiendo el método no paramétrico propuesto por las guías del CLSI. ResultadosNo hubo diferencias en los niveles de folato ni vitamina B12 entre sexos ni grupos de edad. Los límites de referencia para el folato fueron 2,2 y 18ng/ml (5-40,7nmol/l), y 213,8 y 763,3pg/ml (158,2-564,8 pmol/l) para la vitamina B12. Estos intervalos difirieron de los propuestos por el fabricante. ConclusionesNuestros resultados subrayan la importancia de obtener valores de referencia en la población a la que da servicio el laboratorio para excluir inequívocamente las deficiencias de folato y vitamina B12." "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0030" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0035" "titulo" => "Objetivo" ] 2 => array:2 [ "identificador" => "abst0040" "titulo" => "Método" ] 3 => array:2 [ "identificador" => "abst0045" "titulo" => "Resultados" ] 4 => array:2 [ "identificador" => "abst0050" "titulo" => "Conclusiones" ] ] ] ] "multimedia" => array:5 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">• Recent disease \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">• Recent surgery with hospital admission \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">• Hypertension \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">• Genetic diseases \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">• Pregnancy \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">• Breast feeding \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">• Alcohol intake \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">• Tobacco smoking \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">• Drug abuse \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">• Treatment with therapeutic drugs \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">• Use of vitamin supplements \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">• Obesity \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">• Special diets \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1789150.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Exclusion criteria applied for selection of individuals." ] ] 1 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Values represent arithmetic means. Standard deviations are shown in brackets. Concentrations are expressed in the conventional units used in our laboratory. Conversion factors into international units are 2.26 for folate and 0.74 for vitamin B12." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Male (87) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Female (54) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Total (141) \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Age mean (years) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">43.03 (11.1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">40 (13.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">41.87 (12.1) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Folate (ng/mL) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7.79 (3.8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6.5 (3.7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7.3 (3.8) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Vitamin B12 (pg/mL) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">396 (125.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">412.2 (159.91) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">402.2 (139.34) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1789151.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Descriptive characteristics of the sample." ] ] 2 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at3" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Values represent arithmetic means. Standard deviations are shown in brackets. Concentrations are expressed in the conventional units used in our laboratory. Conversion factors into international units are 2.26 for folate and 0.74 for vitamin B12." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">18–34 years \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">35–49 years \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">50–65 years \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Folate (ng/mL) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5.1 (3.2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7.6 (3.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">8.6 (3.9) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Vitamin B12 (pg/mL) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">397.8 (127.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">400.3 (146.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">408.9 (145) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1789152.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Concentrations of folate and vitamin B12 in different age groups." ] ] 3 => array:8 [ "identificador" => "tbl0020" "etiqueta" => "Table 4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at4" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Calculated reference intervals. Concentrations are expressed in the conventional units used in our laboratory. Conversion factors into international units are 2.26 for folate and 0.74 for vitamin B12." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Range \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Median \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Normality \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Percentile 2.5 (CI 90%) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Percentile 97.5 (CI 90%) \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Folate \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.63–19.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6.83 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No (p=0.045) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2.2 (1.65–2.53) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">18 (14.96–19.02) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Vitamin B12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">150.6–929.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">377.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Yes (0.119) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">213.8 (153.74–241.37) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">763.3 (650.71–915.98) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1789154.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Calculated reference intervals for folate and vitamin B12." ] ] 4 => array:8 [ "identificador" => "tbl0025" "etiqueta" => "Table 5" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at5" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Reference values claimed by the manufacturer. Concentrations are expressed in the conventional units used in our laboratory. Conversion factors into international units are 2.26 for folate and 0.74 for vitamin B12." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Median \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Percentile 2.5 \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Percentile 97.5 \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Folate (ng/mL) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">9.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">18.7 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Vitamin B12 (pg/mL) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">425 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">197 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">771 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1789149.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Reference intervals claimed by the manufacturer." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:21 [ 0 => array:3 [ "identificador" => "bib0110" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Folate (folic acid) and vitamin B12" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "J.M. Scott" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "LibroEditado" => array:5 [ "titulo" => "Human nutrition and dietetics" "paginaInicial" => "271" "paginaFinal" => "280" "edicion" => "10th ed." "serieFecha" => "2003" ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0115" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Folate and vitamin B12 interrelationships; links to disease risk" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "A.M. Molloy" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "LibroEditado" => array:5 [ "titulo" => "Folate in health and disease" "paginaInicial" => "381" "paginaFinal" => "408" "edicion" => "2nd ed." 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Valores de referencia de ácido fólico y vitamina B12 séricos en una población española, utilizando un método de electroquimioluminiscencia

José Luis Martín Calderóna,

Corresponding author

jlmartinc@sescam.jccm.es

Corresponding author.

, Luis Caballeroa, Fernando Solanob, Fernando Bustosa

a Department of Clinical Chemistry, Hospital Nuestra Señora del Prado, Talavera de la Reina, Spain

b Department of Haematology, Hospital Nuestra Señora del Prado, Talavera de la Reina, Spain

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            "entidad" => "Department of Clinical Chemistry&#44; Hospital Nuestra Se&#241;ora del Prado&#44; Talavera de la Reina&#44; Spain"
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            "entidad" => "Department of Haematology&#44; Hospital Nuestra Se&#241;ora del Prado&#44; Talavera de la Reina&#44; Spain"
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        "titulo" => "Valores de referencia de &#225;cido f&#243;lico y vitamina B12 s&#233;ricos en una poblaci&#243;n espa&#241;ola&#44; utilizando un m&#233;todo de electroquimioluminiscencia"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Folate and vitamin B<span class="elsevierStyleInf">12</span> are water soluble vitamins involved in one carbon transfer &#40;methylation&#41; reactions necessary for the production of monoamine neurotransmitters&#44; phospholipids and the nucleotides used in DNA synthesis&#46;<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">1&#8211;5</span></a> Vitamin B<span class="elsevierStyleInf">12</span> or folate depletion both increase homocysteine levels&#44; being high circulating levels of homocysteine often consequence of an inadequate status of these vitamins&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">6</span></a> Hyperhomocysteinaemia has been associated with cardiovascular&#44; haematological and neurological diseases&#46;<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">6&#44;7</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Deficiency of folate or of cobalamin may cause different types of disorders&#44; mainly haematological disorders<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">7</span></a> such as anaemia and macrocytosis&#44; but also others as memory disturbances&#44; delirium&#44; mood disorders and psychoses&#46;<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">8&#44;9</span></a> Folate and vitamin B<span class="elsevierStyleInf">12</span> deficiencies are still important problems worldwide&#46; The difficulty to establish consensus levels is due to the fact that serum concentrations of these vitamins differ according to age&#44; gender and other variables&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">6</span></a> Vitamin B<span class="elsevierStyleInf">12</span> levels decrease with age&#44; being clinical and subclinical deficiency more prevalent in the elderly&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">10</span></a> Epidemiological data suggest an estimated prevalence of at least 10&#37; of individuals over 60 years&#46;<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">5&#44;11</span></a> Age influence is not so clear-cut in the case of folate levels&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">12</span></a> In addition diet&#44; habits&#44; and physiological and pathological factors influence cobalamin and folate status&#46; For instance&#44; low vitamin B<span class="elsevierStyleInf">12</span> levels are more frequent in vegetarians&#44;<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">10&#44;13</span></a> in patients with gastrointestinal diseases&#44;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">14</span></a> and in individuals with high alcohol consumption or with renal failure&#46;<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">10&#44;14</span></a> Folate status is also negatively influenced by dietary&#44; pathological &#40;alcoholism&#44; depression&#41; and pharmacological &#40;anticonvulsants&#41; factors&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">15</span></a> Variability is further enhanced by the compulsory fortification of flour with folate and vitamin B<span class="elsevierStyleInf">12</span> dictated by some government agencies&#46;<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">5&#44;15</span></a> As a consequence&#44; prevalence rates for folate and vitamin B<span class="elsevierStyleInf">12</span> deficiencies vary considerably across different studies&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">12</span></a> Besides the aforementioned factors that promote variability&#44; it is important to take also into account methodological differences&#44; especially when immunoassays are used&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">The aim of this work is to define the reference values for serum folate and vitamin B<span class="elsevierStyleInf">12</span> in our population&#46; According to Horn and Pesce&#44;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">16</span></a> reference intervals are the most widely used medical decision-making tools&#46; Ideally&#44; all clinical laboratories should determine their own reference values&#46; However&#44; most of them do not&#44; due to the fact that the establishment of reliable reference intervals is a highly demanding activity&#44;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">17</span></a> and therefore the usual practice is to adopt the intervals provided in the manufacturer&#39;s inserts&#46; We have calculated reference intervals for a population from Central Spain using an electrochemiluminiscent method &#40;Roche Diagnostics&#41; in a Modular E-170 analyzer&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Materials and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Patients</span><p id="par0020" class="elsevierStylePara elsevierViewall">One hundred and forty one healthy volunteers aged 18&#8211;65 years were selected among blood donors of our hospital&#46; Written informed consent was obtained from all of them&#46; Abuse drug consumers&#44; smokers and alcohol drinkers were excluded from the study&#46; The individuals did not have noticeable previous disease&#44; and were not being treated with prescription medications or vitamin supplements at the moment of inclusion&#46; <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> shows the exclusion criteria used for patient selection&#46; Blood was collected in serum separator tubes and serum samples obtained after centrifugation at 1000<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">g</span> during 10<span class="elsevierStyleHsp" style=""></span>min&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Biochemical analysis</span><p id="par0025" class="elsevierStylePara elsevierViewall">Vitamin B<span class="elsevierStyleInf">12</span> and folate levels were measured using a competitive electrochemiluminiscent immunoassay in a Modular E170 analyzer &#40;ROCHE DIAGNOSTICS<span class="elsevierStyleSup">&#174;</span>&#44; Manheim&#44; Germany&#41;&#46; In this method the sample is first pretreated to release vitamin B<span class="elsevierStyleInf">12</span> and folate from their carrier proteins&#46; The sample is then incubated with a ruthenium-labelled protein &#40;intrinsic factor in the vitamin B<span class="elsevierStyleInf">12</span> assay and folate binding protein in the folate assay&#41;&#44; giving rise to an analyte-protein complex whose concentration depends on the concentration of analyte in the sample&#46; Subsequently&#44; streptavidin-covered microparticles and biotin-labelled analyte are added&#46; The latter occupies the remaining free binding sites on the ruthenium-labelled protein&#44; and the resulting complex binds to the solid phase due to the interaction between biotin and streptavidin&#46; The microparticles attach then to the surface of an electrode due to magnetic forces&#44; non-bound components are washed away and&#44; finally&#44; an electric current is applied&#44; which induces a chemiluminiscent reaction whose intensity is proportional to vitamin B<span class="elsevierStyleInf">12</span> or folate concentration&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Statistical analysis</span><p id="par0030" class="elsevierStylePara elsevierViewall">Data analysis was performed using the software package Medcalc 11&#46;3 &#40;Ostend&#44; Belgium&#41;&#46; Reference intervals were calculated using the non-parametric percentile method&#44; following the recommendations of the Clinical Laboratory Standards Institute document CLSI C28 A3&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">18</span></a> The presence of outliers was assessed using the Dixon&#39;s test&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">16</span></a> Kolmogorov&#8211;Smirnov&#39;s test was used to evaluate the Gaussian distribution&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Additionally&#44; we examined if it was possible to partition reference values according to sex or age&#46; The sample was split in three age categories&#58; &#40;I&#41; 18&#8211;34 years&#59; &#40;II&#41; 25&#8211;49 years and &#40;III&#41; 50&#8211;65 years&#46; Assessment of differences between these groups was done using the Harris and Boyd criterion&#44;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">19</span></a> according to which separate intervals must be established if the ratio between the subgroup standard deviations is greater than 1&#46;5&#46;</p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Results</span><p id="par0040" class="elsevierStylePara elsevierViewall">The sample representing our population was composed of 141 healthy volunteers aged 18&#8211;65 years&#44; 87 of them male &#40;61&#46;7&#37;&#41; and 54 female &#40;38&#46;3&#37;&#41;&#46; The age arithmetic mean was 41&#46;9 years &#40;median 43&#44; standard deviation 12&#46;1&#41;&#46; The descriptive characteristics of the study group are shown on <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0045" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a> shows the results when the sample was split in age groups&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0050" class="elsevierStylePara elsevierViewall">Kolmogorov&#8211;Smirnov&#39;s test showed a Gaussian distribution for vitamin B<span class="elsevierStyleInf">12</span> but not for folate levels &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46; The reference interval for folate ranged from 2&#46;2 to 18<span class="elsevierStyleHsp" style=""></span>ng&#47;mL &#40;5&#8211;40&#46;7<span class="elsevierStyleHsp" style=""></span>nmol&#47;L&#41;&#44; and in the case of vitamin B<span class="elsevierStyleInf">12</span> from 213&#46;8 to 763&#46;3<span class="elsevierStyleHsp" style=""></span>pg&#47;mL &#40;158&#46;2&#8211;564&#46;8<span class="elsevierStyleHsp" style=""></span>pmol&#47;L&#41;&#46; These reference intervals are shown on <a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#44; where the numbers in brackets represent the 90&#37; confidence intervals&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><p id="par0055" class="elsevierStylePara elsevierViewall">Application of the Harris and Boyd&#39;s method leads us to conclude that there are no significant differences for folate or vitamin B<span class="elsevierStyleInf">12</span> concentration among different sex or age groups&#44; as standard deviation ratios are under 1&#46;5 in every case&#46; Given that folate values did not show a Gaussian distribution logarithmic normal transformation was carried out for this variable before applying the Harris and Boyd&#39;s approximation&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">Reference intervals claimed by the manufacturer are shown in <a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a>&#46;</p><elsevierMultimedia ident="tbl0025"></elsevierMultimedia></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Discussion</span><p id="par0065" class="elsevierStylePara elsevierViewall">One of the critical aspects of the practice of clinical laboratory medicine is the assessment of test results to determine whether patients are healthy or&#44; on the contrary&#44; subject to some pathological condition&#46; Thus&#44; the inclusion of reference intervals in clinical laboratory reports is mandatory&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">17</span></a> Each laboratory should produce its own reference values and estimate the corresponding reference intervals&#46;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">20&#44;21</span></a> However&#44; this recommendation seems to have had limited impact in most clinical laboratories&#44;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">17</span></a> the usual practice being to adopt values included in the reagent inserts&#46; This is due to the fact that the calculation of an adequate reference interval is a highly demanding and difficult activity&#46;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">16&#44;17</span></a> The Clinical Laboratory Standard Institute &#40;CLSI&#41; and the International Federation of Clinical Chemistry &#40;IFCC&#41; recommend the inclusion of at least 120 individuals in the calculation of a reference interval<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">16&#44;18&#44;20</span></a>&#59; this recommendation is widely fulfilled in our sample &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>141&#41;&#46; Establishing reference intervals has always been a challenging task&#44; as significant differences may exist between ethnic&#44; gender or age groups&#44; and as they may also vary depending on specimen collection techniques&#44; test assays&#44; and other factors&#46; This variability is even greater in the cases of folate and vitamin B<span class="elsevierStyleInf">12</span> which&#44; apart from the aforementioned factors&#44; can also be influenced by diet&#44; drug therapies&#44; and policies of grain fortification&#46; This reinforces the need of elaborating reference intervals for this analytes by every individual clinical laboratory&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">In our case&#44; the manufacturer&#39;s change of the composition of folate and vitamin B<span class="elsevierStyleInf">12</span> reagents<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">21</span></a> &#40;folate III&#44; vitamin B<span class="elsevierStyleInf">12</span> II&#41; has led to lower results than the ones we used to obtain with previous versions &#40;particularly for folate&#41;&#46; In spite of this fact&#44; the reference intervals stated in the vendor&#39;s insert are similar to the previous ones&#46; This has prompted us to produce our own reference values&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">As we expected&#44; in the case of folate we obtained a 2&#46;5 percentile considerably lower than the one claimed by the vendor &#40;2&#46;2 vs&#46; 4&#46;6<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&#44; or 5 vs&#46; 10&#46;2<span class="elsevierStyleHsp" style=""></span>nmol&#47;L&#41;&#44; although upper limits were similar&#46; The difference was not so marked in the case of vitamin B<span class="elsevierStyleInf">12</span>&#44; but our 2&#46;5 percentile was also lower than that claimed by the manufacturer &#40;197 vs&#46; 213&#46;8<span class="elsevierStyleHsp" style=""></span>pg&#47;mL&#44; or 145&#46;8 vs&#46; 158&#46;2<span class="elsevierStyleHsp" style=""></span>pmol&#47;L&#41;&#46; This fact reinforces the need of each clinical laboratory to build its own reference intervals&#46; When we applied Harris and Boyd method<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">19</span></a> to our data we found no age- or sex-related differences between serum vitamin levels&#46; Although the influence of age in vitamin B<span class="elsevierStyleInf">12</span> status is well known&#44;<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">10&#8211;13</span></a> our sample did not include elderly people&#44; a fact that explains the lack of difference between subclasses&#46; Sex differences are not so clear cut in previously published studies&#44;<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">6&#44;12</span></a> and accordingly we found no relation between reference intervals and sex&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">A limitation of our study is that we did not measure other metabolites such as homocysteine&#44; methyl malonic acid or red blood content of folate&#46; Although this would have exceeded the scope of our study&#44; it would have been interesting in order to define more precisely the cobalamin and folate status in our population&#46; Unfortunately&#44; we have no available methods for the routine determination of these analytes in our laboratory&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Ethical disclosures</span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Protection of human and animal subjects</span><p id="par0085" class="elsevierStylePara elsevierViewall">The authors declare that no experiments were performed on humans or animals for this study&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Confidentiality of data</span><p id="par0090" class="elsevierStylePara elsevierViewall">The authors declare that no patient data appear in this article&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Right to privacy and informed consent</span><p id="par0095" class="elsevierStylePara elsevierViewall">Patient data are not shown in this article&#46;</p></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Conflict of interest</span><p id="par0100" class="elsevierStylePara elsevierViewall">The Authors declare that they do not have any conflict of interest with the company which provides reagents and instrumentations&#46;</p></span></span>"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Despite being the most widely used medical decision-making tool&#44; reference intervals are not usually determined by clinical laboratories&#44; due to the highly demanding activities and costly process it involves&#46; However&#44; scientific societies encourage individual clinical laboratories to establish their own reference values&#46; This is especially important in the cases of folate and vitamin B<span class="elsevierStyleInf">12</span>&#44; due to strong differences in vitamin status among different populations&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Objective</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Our aim is to establish reference intervals for folate and vitamin B<span class="elsevierStyleInf">12</span> levels in a healthy blood donor population using an electrochemiluminiscent method &#40;ROCHE DIAGNOSTICS&#41;&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Method</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Folate and vitamin B<span class="elsevierStyleInf">12</span> levels were measured in 141 healthy blood donors aged between 18 and 65 years&#46; Biochemical analyses were performed using a Modular E170 analyzer &#40;ROCHE DIAGNOSTICS&#41; and an electrochemiluminiscent method&#46; Reference intervals were calculated with a non-parametric percentile method following the CLSI guidelines&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Results</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">There were not significant differences in folate or cobalamin levels between age or sex subgroups&#46; The limits of the reference interval for folate were 2&#46;2 and 18<span class="elsevierStyleHsp" style=""></span>ng&#47;mL &#40;5&#8211;40&#46;7<span class="elsevierStyleHsp" style=""></span>nmol&#47;L&#41;&#44; and 213&#46;8 and 763&#46;3<span class="elsevierStyleHsp" style=""></span>pg&#47;mL &#40;158&#46;2&#8211;564&#46;8<span class="elsevierStyleHsp" style=""></span>pmol&#47;L&#41; for vitamin B<span class="elsevierStyleInf">12</span>&#46; These intervals differed from those claimed by the manufacturer&#46;</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Conclusions</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Our results emphasize the convenience of building reference values based on the population served by the laboratory&#44; in order to unequivocally rule out deficiencies of folate or vitamin B<span class="elsevierStyleInf">12&#46;</span></p></span>"
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            "identificador" => "abst0025"
            "titulo" => "Conclusions"
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        "resumen" => "<span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Introducci&#243;n</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">A pesar de ser una de las herramientas m&#225;s usadas en la toma de decisiones m&#233;dicas&#44; los intervalos de referencia son raramente determinados en los laboratorios&#44; debido a que es una labor compleja en t&#233;rminos de tiempo&#44; esfuerzo y coste&#46; Sin embargo las sociedades cient&#237;ficas recomiendan que los laboratorios establezcan sus propios valores de referencia&#46; Esto es especialmente importante para el folato y la vitamina B12&#44; debido a las grandes diferencias entre poblaciones&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Objetivo</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Nuestro prop&#243;sito es establecer los valores de referencia en una poblaci&#243;n de donantes sanos&#44; mediante un m&#233;todo electroquimioluminiscente &#40;Roche Diagnostics&#41;&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">M&#233;todo</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Los niveles de folato y vitamina B12 se midieron en una muestra integrada por 141 donantes sanos de una edad comprendida entre 18 y 65 a&#241;os&#46; Los an&#225;lisis bioqu&#237;micos se realizaron en un analizador Modular E170 &#40;Roche Diagnostics&#41;&#46; Los intervalos de referencia se calcularon siguiendo el m&#233;todo no param&#233;trico propuesto por las gu&#237;as del CLSI&#46;</p></span> <span id="abst0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Resultados</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">No hubo diferencias en los niveles de folato ni vitamina B12 entre sexos ni grupos de edad&#46; Los l&#237;mites de referencia para el folato fueron 2&#44;2 y 18<span class="elsevierStyleHsp" style=""></span>ng&#47;ml &#40;5-40&#44;7<span class="elsevierStyleHsp" style=""></span>nmol&#47;l&#41;&#44; y 213&#44;8 y 763&#44;3<span class="elsevierStyleHsp" style=""></span>pg&#47;ml &#40;158&#44;2-564&#44;8 pmol&#47;l&#41; para la vitamina B<span class="elsevierStyleInf">12</span>&#46; Estos intervalos difirieron de los propuestos por el fabricante&#46;</p></span> <span id="abst0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conclusiones</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Nuestros resultados subrayan la importancia de obtener valores de referencia en la poblaci&#243;n a la que da servicio el laboratorio para excluir inequ&#237;vocamente las deficiencias de folato y vitamina B12&#46;</p></span>"
        "secciones" => array:5 [
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            "identificador" => "abst0030"
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          2 => array:2 [
            "identificador" => "abst0040"
            "titulo" => "M&#233;todo"
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            "identificador" => "abst0045"
            "titulo" => "Resultados"
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            "identificador" => "at1"
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        "tabla" => array:1 [
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">&#8226; Recent disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">&#8226; Recent surgery with hospital admission&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">&#8226; Hypertension&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">&#8226; Genetic diseases&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">&#8226; Pregnancy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">&#8226; Breast feeding&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">&#8226; Alcohol intake&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">&#8226; Tobacco smoking&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">&#8226; Drug abuse&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">&#8226; Treatment with therapeutic drugs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">&#8226; Use of vitamin supplements&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">&#8226; Obesity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">&#8226; Special diets&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Exclusion criteria applied for selection of individuals&#46;</p>"
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      1 => array:8 [
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        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
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        "detalles" => array:1 [
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          "leyenda" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Values represent arithmetic means&#46; Standard deviations are shown in brackets&#46; Concentrations are expressed in the conventional units used in our laboratory&#46; Conversion factors into international units are 2&#46;26 for folate and 0&#46;74 for vitamin B<span class="elsevierStyleInf">12&#46;</span></p>"
          "tablatextoimagen" => array:1 [
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              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Male &#40;87&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Female &#40;54&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Total &#40;141&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Age mean &#40;years&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">43&#46;03 &#40;11&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">40 &#40;13&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">41&#46;87 &#40;12&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Folate &#40;ng&#47;mL&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">7&#46;79 &#40;3&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6&#46;5 &#40;3&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">7&#46;3 &#40;3&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Vitamin B<span class="elsevierStyleInf">12</span> &#40;pg&#47;mL&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">396 &#40;125&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">412&#46;2 &#40;159&#46;91&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">402&#46;2 &#40;139&#46;34&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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              ]
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        "descripcion" => array:1 [
          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Descriptive characteristics of the sample&#46;</p>"
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      2 => array:8 [
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        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
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            "identificador" => "at3"
            "detalle" => "Table "
            "rol" => "short"
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Values represent arithmetic means&#46; Standard deviations are shown in brackets&#46; Concentrations are expressed in the conventional units used in our laboratory&#46; Conversion factors into international units are 2&#46;26 for folate and 0&#46;74 for vitamin B<span class="elsevierStyleInf">12&#46;</span></p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">18&#8211;34 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">35&#8211;49 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">50&#8211;65 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Folate &#40;ng&#47;mL&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5&#46;1 &#40;3&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">7&#46;6 &#40;3&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">8&#46;6 &#40;3&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Vitamin B<span class="elsevierStyleInf">12</span> &#40;pg&#47;mL&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">397&#46;8 &#40;127&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">400&#46;3 &#40;146&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">408&#46;9 &#40;145&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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        "descripcion" => array:1 [
          "en" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Concentrations of folate and vitamin B<span class="elsevierStyleInf">12</span> in different age groups&#46;</p>"
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      3 => array:8 [
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        "etiqueta" => "Table 4"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at4"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">Calculated reference intervals&#46; Concentrations are expressed in the conventional units used in our laboratory&#46; Conversion factors into international units are 2&#46;26 for folate and 0&#46;74 for vitamin B<span class="elsevierStyleInf">12&#46;</span></p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Range&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Median&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Normality&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Percentile 2&#46;5 &#40;CI 90&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Percentile 97&#46;5 &#40;CI 90&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Folate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;63&#8211;19&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6&#46;83&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;045&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&#46;2 &#40;1&#46;65&#8211;2&#46;53&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">18 &#40;14&#46;96&#8211;19&#46;02&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Vitamin B<span class="elsevierStyleInf">12</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">150&#46;6&#8211;929&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">377&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Yes &#40;0&#46;119&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">213&#46;8 &#40;153&#46;74&#8211;241&#46;37&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">763&#46;3 &#40;650&#46;71&#8211;915&#46;98&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "en" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">Calculated reference intervals for folate and vitamin B<span class="elsevierStyleInf">12</span>&#46;</p>"
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          "leyenda" => "<p id="spar0095" class="elsevierStyleSimplePara elsevierViewall">Reference values claimed by the manufacturer&#46; Concentrations are expressed in the conventional units used in our laboratory&#46; Conversion factors into international units are 2&#46;26 for folate and 0&#46;74 for vitamin B<span class="elsevierStyleInf">12&#46;</span></p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Median&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Percentile 2&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Percentile 97&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Folate &#40;ng&#47;mL&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">9&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">18&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Vitamin B<span class="elsevierStyleInf">12</span> &#40;pg&#47;mL&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">425&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">197&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">771&nbsp;\t\t\t\t\t\t\n
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                            3 => "A&#46; Alum&#225;-Trull&#225;s"
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Article information

ISSN: 18884008
Original language: English

DOI:10.1016/j.labcli.2017.11.002

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Year/Month	Html	Pdf	Total

2024 November	8	0	8
2024 October	92	7	99
2024 September	99	4	103
2024 August	73	5	78
2024 July	38	4	42
2023 March	4	0	4
2022 June	33	4	37
2022 May	52	14	66
2022 April	79	26	105
2022 March	79	24	103
2022 February	62	14	76
2022 January	89	17	106
2021 December	67	22	89
2021 November	69	10	79
2021 October	101	17	118
2021 September	76	13	89
2021 August	71	13	84
2021 July	65	12	77
2021 June	57	14	71
2021 May	105	8	113
2021 April	265	19	284
2021 March	161	10	171
2021 February	95	19	114
2021 January	90	8	98
2020 December	80	16	96
2020 November	89	22	111
2020 October	75	12	87
2020 September	81	11	92
2020 August	43	10	53
2020 July	52	13	65
2020 June	68	15	83
2020 May	43	7	50
2020 April	35	13	48
2020 March	10	1	11
2020 January	1	0	1
2019 December	1	2	3
2019 July	0	2	2
2019 May	1	0	1
2019 March	4	2	6
2019 February	3	6	9
2019 January	4	8	12
2018 December	3	6	9
2018 November	2	4	6
2018 October	12	4	16
2018 September	8	10	18
2018 August	13	0	13
2018 July	33	3	36
2018 April	0	1	1
2018 March	0	2	2
2018 February	0	5	5
2018 January	0	4	4
2017 December	0	9	9

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