Estimation Of Reference Intervals Research Articles

Quantitative laboratory results: normal or lognormal distribution?

Abstract The identification of a suitable distribution model is a prerequisite for the parametric estimation of reference intervals and other statistical laboratory tasks. Classification of normal vs. lognormal distributions from healthy populations is easy, but from mixed populations, containing unknown proportions of abnormal results, it is challenging. We demonstrate that Bowley’s skewness coefficient differentiates between normal and lognormal distributions. This classifier is robust and easy to calculate from the quartiles Q1–Q3 according to the formula (Q1 − 2 · Q2 + Q3)/(Q3 − Q1). We validate our algorithm with a more complex procedure, which optimizes the exponent λ of a power transformation. As a practical application, we show that Bowley’s skewness coefficient is suited selecting the adequate distribution model for the estimation of reference limits according to a recent International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) recommendation, especially if the data is right-skewed.

Reference Interval Estimation from Mixed Distributions using Truncation Points and the Kolmogorov-Smirnov Distance (kosmic)

Appropriate reference intervals are essential when using laboratory test results to guide medical decisions. Conventional approaches for the establishment of reference intervals rely on large samples from healthy and homogenous reference populations. However, this approach is associated with substantial financial and logistic challenges, subject to ethical restrictions in children, and limited in older individuals due to the high prevalence of chronic morbidities and medication. We implemented an indirect method for reference interval estimation, which uses mixed physiological and abnormal test results from clinical information systems, to overcome these restrictions. The algorithm minimizes the difference between an estimated parametrical distribution and a truncated part of the observed distribution, specifically, the Kolmogorov-Smirnov-distance between a hypothetical Gaussian distribution and the observed distribution of test results after Box-Cox-transformation. Simulations of common laboratory tests with increasing proportions of abnormal test results show reliable reference interval estimations even in challenging simulation scenarios, when <20% test results are abnormal. Additionally, reference intervals generated using samples from a university hospital’s laboratory information system, with a gradually increasing proportion of abnormal test results remained stable, even if samples from units with a substantial prevalence of pathologies were included. A high-performance open-source C++ implementation is available at https://gitlab.miracum.org/kosmic.

Estimation of Reference Interval of Serum Progesterone During Three Trimesters of Normal Pregnancy in a Tertiary Care Hospital of Kolkata

Estimation of Reference Interval of Serum Progesterone During Three Trimesters of Normal Pregnancy in a Tertiary Care Hospital of Kolkata

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

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

Estimation of reference intervals of insulin resistance (HOMA), insulin sensitivity (Matsuda), and insulin secretion sensitivity indices (ISSI-2) in Polish young people.

Insulin resistance is becoming an increasingly widespread problem worldwide. For its determination indirect indices of insulin resistance or insulin sensitivity have used. Those indices based on simultaneous measurements of blood glucose and insulin concentrations under fasting conditions or during the Oral Glucose Tolerance Test. The aim of the study was to estimate reliable reference values for the indices used in insulin resistance diagnosis. Materials and method. 191 selected participants, aged 18-31, were enrolled into the reference population. 130 participants from the reference population with fasting glucose ≤5.5 mmol/L, BMI<25 kg/m2, and without metabolic syndrome, were finally included in the reference group. The following insulin resistance indices were calculated: HOMA1-IR, HOMA2, HOMA2 from C-peptide, QUICKI, Matsuda Index and Insulin Secretion-Sensitive Index-2. Determination of reference intervals for indirect indices of insulin resistance was conducted in accordance with the C28-A3 procedure recommended by the Clinical & Laboratory Standards Institute (CLSI). Results. The reference intervals for indirect insulin resistance indices examined according to CLSI protocol were: ≤4.00, ≤2.27, ≤4.10, ≥0.31 for HOMA1-IR, HOMA2, HOMA2 C-pep., and QUICKI, respectively. For insulin sensitivity, the value of the Matsuda Index was established as ≥3.19 and for beta cell pancreatic function ISSI-2 as ≥206. Conclusions. Establishing a reference intervals for these indices enable the proper identification and differentiation of the types of insulin resistance in particular populations. The early detection of metabolic disorders allows for introduction of effective preventive action.

Folate reference interval estimation in the Dutch general population

BackgroundFolate functions as an enzyme co-factor within the one-carbon metabolic pathway, providing key metabolites required for DNA synthesis and methylation. Hence, insufficient intake of folate can negatively affect health. As correct interpretation of folate status is dependent on a well-established reference interval, we set out to perform a new estimation following the restandardization of the Roche folate assay against the international folate standard. Materials and methodsThe folate reference interval was estimated using samples obtained from the Dutch population-based Lifelines cohort. The reference interval was estimated using two methods: a nonparametric estimation combined with bootstrap resampling and by fitting the data to a gamma distribution. The lower reference limit was verified in a patient cohort by combined measurement of folate and homocysteine. ResultsDependent on the method used for estimation and in- or exclusion of individuals younger than 21 years of age, the lower reference limit ranged from 6.8 to 7.3 nmol/L and the upper reference limit ranged from 26 to 38.5 nmol/L. Applying a lower reference limit of 7.3 nmol/L resulted in the following percentage of folate deficiencies over a period of 12 months: general practitioner 15.5% (IQR 4.0%), general hospital 12.8% (IQR 5.3%), academic hospital 9.6% (IQR 4.3%). ConclusionsWe estimated the folate reference interval in the Dutch general population which is not affected by a folic acid fortification program and verified the obtained lower reference limit by homocysteine measurements. Based on our results, we propose a folate reference interval independent of age of 7.3–38.5 nmol/L

Reference interval by the indirect approach of serum thyrotropin (TSH) in a Mediterranean adult population and the association with age and gender.

Background The serum concentration of thyrotropin (TSH) represents a first-line test in diagnostic algorithms. The estimation of TSH reference intervals (RIs) is still a matter of debate due to the high prevalence of subclinical disease making difficult the definition of truly healthy subjects. The aim of this study was to estimate TSH RIs in healthy subjects and to evaluate the effect of age and gender on TSH concentration. Methods Forty-four thousand one hundred and fifty-six TSH data were collected between July 2012 and April 2018 at the Department of Laboratory Medicine, University-Hospital, Palermo. Common and sex-specific RIs were estimated by Arzideh's indirect method after exclusion of individuals younger than 15 years, subjects with repeated TSH tests and with abnormal free thyroxine (fT4), free triiodothyronine (fT3) or anti-thyroid-peroxidase antibodies. The combined effect of age and gender on TSH values was evaluated. Results RIs estimated in the selected individuals (n = 22602) were, respectively, 0.18-3.54 mIU/L (general), 0.19-3.23 mIU/L (men) and 0.18-3.94 mIU/L (women). Women showed significantly higher median TSH than men (1.46 vs. 1.39 mIU/L; p < 0.0001). Both in men and in women, median TSH decreased along with age; however, although up to 60 years in both men and women showed similar values, afterwards women showed constantly higher TSH than men. Accordingly, statistical analysis showed a significant interaction between gender and age (p = 0.001), suggesting that the effect of age on TSH is different between genders. Conclusions Our findings suggest that the indirect method, with appropriate cleaning of data, could be useful to define TSH RIs.

Widespread Incorrect Implementation of the Hoffmann Method, the Correct Approach, and Modern Alternatives.

The Hoffmann method is a procedure for reference interval estimation using routine clinical results. Many authors incorrectly prepare Hoffmann plots on a linear rather than normal probability scale. We explore the consequences. This was investigated algebraically, by random number simulations (45 simulations, n = 100,000 each) and using clinical data sets. Strategies compared were: Hoffmann's method as originally and incorrectly implemented, Bhattacharya's method, and maximum likelihood (ML). All R source code and data sets are provided. As the proportion of healthy individuals approaches 1, the incorrect approach generates reference interval estimates of approximately μH ± 1.19 σH delineating the central 77% of the healthy subpopulation, not the central 95%. Inappropriately narrow reference interval estimates were seen on random simulations and clinical data sets. ML methods performed best. The erroneous variant Hoffmann method should not be used. ML methods outperform others and are not restricted by Gaussian assumptions.

Algorithm on age partitioning for estimation of reference intervals using clinical laboratory database exemplified with plasma creatinine.

We describe an algorithm to determine age-partitioned reference intervals (RIs) exemplified for creatinine using data collection from the clinical laboratory database. The data were acquired from the test results of creatinine of 164,710 outpatients aged <18 years in Beijing Children's Hospital laboratories' databases between January 2016 and December 2016. The tendency of serum creatinine with age was examined visually using box plot by gender first. The age subgroup was divided automatically by the decision tree method. Subsequently, the statistical tests of the difference between subgroups were performed by Harris-Boyd and Lahti methods. A total of 136,546 samples after data cleaning were analyzed to explore the partition of age group for serum creatinine from birth to 17 years old. The suggested age partitioning of RIs for creatinine by the decision tree method were for eight subgroups. The difference between age subgroups was demonstrated to be statistically significant by Harris-Boyd and Lahti methods. In addition, the results of age partitioning for RIs estimation were similar to the suggested age partitioning by the Canadian Laboratory Initiative in Pediatric Reference Intervals study. Lastly, a suggested algorithm was developed to provide potential methodological considerations on age partitioning for RIs estimation. Appropriate age partitioning is very important for establishing more accurate RIs. The procedure to explore the age partitioning using clinical laboratory data was developed and evaluated in this study, and will provide more opinions for designing research on establishment of RIs.

Reference intervals for thyrotropin in an area of Northern Italy: the Pordenone thyroid study (TRIPP).

Thyrotropin (TSH) is the most accurate marker of thyroid dysfunction in the absence of pituitary or hypothalamic disease. Studies on TSH reference intervals (RIs) showed wide inter-individual variability and prompted an intense debate about the best estimation of TSH RIs. We performed a population study on TSH RIs, using current data stored in the laboratory information system (LIS), at the Hospital Department of Laboratory Medicine, Pordenone (Italy), historically an area of mild-moderate iodine deficiency with a relatively high goiter prevalence. 136,650 individuals constituted the final sample. A TSH immunoassay was performed on fasting serum samples with the Dimension Vista 1500 analyzer (Siemens Healthineers). We adopted the Kairisto's procedure to analyze TSH data downloaded by the LIS, applying the indirect strategy for deriving RIs. TSH RIs of the entire population were 0.32-3.36mIU/L with a distribution skewed towards higher values. RIs were 0.26-3.61mIU/L for females, and 0.32-3.01mIU/L for males. Unlike other studies, TSH median levels progressively decreased from 0-4 to 85-104years in the overall population, both in male and in female subgroups, showing an inverse correlation between TSH and age in all groups. This study is the first to analyze a high percentage (40%) of individuals from an ethnically homogenous Caucasian population. The results obtained emphasize the opportunity to define the TSH RIs according to age, gender and race, in addition to assay methods, and provide further insight about the possible role of iodine status.

Reference interval estimation: Methodological comparison using extensive simulations and empirical data

ObjectiveTo statistically compare and evaluate commonly used methods of estimating reference intervals and to determine which method is best based on characteristics of the distribution of various data sets. Design and methodsThree approaches for estimating reference intervals, i.e. parametric, non-parametric, and robust, were compared with simulated Gaussian and non-Gaussian data. The hierarchy of the performances of each method was examined based on bias and measures of precision. The findings of the simulation study were illustrated through real data sets. ResultsIn all Gaussian scenarios, the parametric approach provided the least biased and most precise estimates. In non-Gaussian scenarios, no single method provided the least biased and most precise estimates for both limits of a reference interval across all sample sizes, although the non-parametric approach performed the best for most scenarios. The hierarchy of the performances of the three methods was only impacted by sample size and skewness. Differences between reference interval estimates established by the three methods were inflated by variability. ConclusionsWhenever possible, laboratories should attempt to transform data to a Gaussian distribution and use the parametric approach to obtain the most optimal reference intervals. When this is not possible, laboratories should consider sample size and skewness as factors in their choice of reference interval estimation method. The consequences of false positives or false negatives may also serve as factors in this decision.

Direct Estimation of Reference Intervals for Thyroid Parameters in the Republic of Srpska.

summaryBackgroundThe aim of this study was to determine the reference values for thyrotropin (TSH), thyroid hormones (total and free thyroxine, T4 and fT4; total and free triiodothyronine, T3 and fT3), thyroglobulin (Tg) and thyroid antibodies (thyroid peroxidase, TPOAb and thyroglobulin antibody, TgAb) in the population of the Republic of Srpska.MethodsA total of 250 euthyroid subjects were enrolled in this study. A direct method for choosing reference subjects was used to establish reference intervals. The hormones and thyroid antibodies were measured by an electrochemiluminescence immunoassay method (ECLIA, Roche Diagnostics, Mannheim, Germany). We calculated the reference intervals by MedCalc, version 12.1.4.0 (MedCalc software, Belgium) as recommended by the IFCC (CLSI C28-A3).ResultsUsing guidelines recommended by the National Academy of Clinical Biochemistry (NACB) and based on standard statistical approaches, the reference intervals derived for TSH, fT4, T4, fT3, T3 were 0.75–5.32 mIU/L, 12.29–20.03 pmol/L, 73.49–126,30 nmol/L, 4.11–6.32 pmol/L, 1.15–2.32 nmol/L and for Tg, TPOAb, TgAb were 3.63–26.00 μg/L, <18.02 mIU/L, < 98.00 mIU/L, respectively. We found a significant difference (p<0.05) in TSH and fT3 values between different age groups as well as in T4, fT4 and fT3 values between ge nder groups.ConclusionsThe established reference values for the population of the Republic of Srpska were significantly different from the values recommended by the manufacturer of reagents (Roche Diagnostics). Our results showed that a laboratory needs to establish its own reference values in order to set up a proper diagnosis, as well as to treat patients successfully.

Estimation of hematological reference intervals for clinically healthy Iraqi local goats using reference value advisor

A cross section study was conducted to investigate the effect of sex and to establish reference values for hematological parameters in the Iraqi local goats in order to form a basis for clinical interpretation. A total of 120 goats (59 male and 61 female) were enrolled in the current study during the period from November to December 2016. The animal’s age ranged from 1 to 5 years. Statistical analysis showed that Hct, MCV, and WBC means were significantly (P < 0.05) higher in males as compared with females. On the other hand, the MCHC in females was significantly (P < 0.05) higher than males. Hematological parameters were measured and reference interval (RI) was determined by using Reference Value Advisor. The results revealed that the RI of hematological parameters of the present study as following: hematocrit (RBC) 9.00–18.00 × 106; Hb 9.00–10.99 g/dl; hematocrit (Hct) 24.00–35.00%, corpuscular hemoglobin concentration (MCHC) 29.41–42.00 g/dl; corpuscular hemoglobin (MCH) 4.41–6.27 pg; corpuscular volume (MCV) 13.15–19.69 fl; and WBC 7.50–13.98 × 103. The results showed that the effect of age and sex was significant (P < 0.05) on most of hematological parameters. It could be concluded that age and sex should be considered in the estimation of hematological parameters, to ensure accurate interpretation of the parameters in goats. The difference between RI of Iraqi local goats and the general reference intervals could be attributed to breed-specific variation. The findings of the present study could serve as reference values for hematological parameters of Iraqi local goats and could assist the veterinarians to interpret laboratory data and to monitor the animal health.

A combined approach to generate laboratory reference intervals using unbalanced longitudinal data.

The interpretation of individual laboratory test results requires the availability of population-based reference intervals. In children, reference interval estimation has to consider frequently the strong age-dependency. Generally, for the construction of reference intervals, a sufficiently large number of independent measurement values is required. Data selections from hospitals or cohort studies often comprise dependencies violating the independence assumption. In this article, we propose a combination of LMS-like (mean, M; coefficient of variation, S; skewness, λ or L) and resampling methods to overcome this drawback. The former is recommended by the World Health Organization (WHO) for the construction of continuous reference intervals of anthropometric measurements in children. The approach allows the inclusion of dependent measurements, for example, repeated measurements per subject. It also provides pointwise confidence envelopes as a measure of reliability. The combination of LMS-type methods and resampling provides a feasible approach to estimate age-dependent percentiles and reference intervals using unbalanced longitudinal data.

Verification of Abbott 25-OH-vitamin D assay on the architect system

ObjectivesAnalytical and clinical verification of both old and new generations of the Abbott total 25-hydroxyvitamin D (25OHD) assays, and an examination of reference Intervals. MethodsDetermination of between-run precision, and Deming comparison between patient sample results for 25OHD on the Abbott Architect, DiaSorin Liaison and AB SCIEX API 4000 (LC-MS/MS). Establishment of uncertainty of measurement for 25OHD Architect methods using old and new generations of the reagents, and estimation of reference interval in healthy Irish population. ResultsFor between-run precision the manufacturer claims 2.8% coefficients of variation (CVs) of 2.8% and 4.6% for their high and low controls, respectively. Our instrument showed CVs between 4% and 6.2% for all levels of the controls on both generations of the Abbott reagents. The between-run uncertainties were 0.28 and 0.36, with expanded uncertainties 0.87 and 0.98 for the old and the new generations of reagent, respectively. The difference between all methods used for patients’ samples was within total allowable error, and the instruments produced clinically equivalent results. The results covered the medical decision points of 30, 40, 50 and 125nmol/L. The reference interval for total 25OHD in our healthy Irish subjects was lower than recommended levels (24–111 nmol/L). ConclusionIn a clinical laboratory Abbott 25OHD immunoassays are a useful, rapid and accurate method for measuring total 25OHD. The new generation of the assay was confirmed to be reliable, accurate, and a good indicator for 25OHD measurement. More study is needed to establish reference intervals that correctly represent the healthy population in Ireland.

Simple estimation of reference intervals from routine laboratory data

Abstract: According to the recommendations of the IFCC and other organizations, medical laboratories should establish or at least adapt their own reference intervals, to make sure that they reflect the peculiar characteristics of the respective methods and patient collectives. In practice, however, this postulate is hard to fulfill. Therefore, two task forces of the DGKL (“AG Richtwerte” and “AG Bioinformatik”) have developed methods for the estimation of reference intervals from routine laboratory data. Here we describe a visual procedure, which can be performed on an Excel sheet without any programming knowledge. Patient values are plotted against the quantiles of the standard normal distribution (so-called QQ plot) using the NORM. INV function of Excel. If the examined population contains mainly non-diseased persons with approximately normally distributed values, the respective dots form a straight line. Very often the values are rather lognormally distributed; in this case the straight line can be detected after logarithmic transformation of the original values. Values, which do not match with the assumed theoretical distribution, deviate from the linear shape and can easily be identified and eliminated. Using the reduced data set, the mean value and standard deviation are calculated and the reference interval (μ±2σ) is estimated. The method yields plausible results with simulated and real data. With the increasing number of results, which do not match with the model, it tends to underestimate the standard deviation. In all cases, where the QQ plot does not yield a substantial linear part, the proposed method is not applicable.

Reference intervals for serum cystatin C and creatinine of an indigenous adult Nigerian population.

Estimation of the glomerular filtration rate (GFR) is important for the evaluation of patients with kidney disease. Some studies suggest that GFR estimated from serum cystatin C (Cys C) is more accurate than that from serum creatinine (SCr). For Cys C to be used for this purpose, normal values need to be determined for various populations. This study determined the serum Cys C levels and reference intervals (RIs) of a Nigerian population. Three hundred and four healthy adult subjects were analysed. Serum Cys C and SCr were determined by particle enhanced turbidimetric immunoassay and modified Jaffe kinetic method respectively. Data were analysed using the Statistical Package for Social Sciences version 17.0 (SPSS for Windows Inc., Chicago, IL, USA). Estimation of RIs was done as per the International Federation of Clinical Chemistry guidelines. The RIs for Cys C were 0.65-1.12 mg/L (median 0.86) for males, 0.62-1.12 mg/L (median 0.85) for females and 0.64-1.12 mg/L (median 0.86) for all the subjects. The RIs for SCr were 73-110 μmol/L (median 89) for males, 65-102 μmol/L (median 82) for females and 66-106 μmol/L (median 86) for all the subjects. There was no significant gender difference in the RIs for serum Cys C, (P > 0.05). The SCr levels and RI were significantly lower in females than in males (P < 0.001). This study has determined the serum Cys C levels and RI of an indigenous healthy adult black population in Nigeria.

Lower reference limits of quantitative cord glucose-6-phosphate dehydrogenase estimated from healthy term neonates according to the Clinical and Laboratory Standards Institute guidelines: a cross sectional retrospective study.

BackgroundPrevious studies have reported the lower reference limit (LRL) of quantitative cord glucose-6-phosphate dehydrogenase (G6PD), but they have not used approved international statistical methodology. Using common standards is expecting to yield more true findings. Therefore, we aimed to estimate LRL of quantitative G6PD detection in healthy term neonates by using statistical analyses endorsed by the International Federation of Clinical Chemistry (IFCC) and the Clinical and Laboratory Standards Institute (CLSI) for reference interval estimation.MethodsThis cross sectional retrospective study was performed at King Abdulaziz Hospital, Saudi Arabia, between March 2010 and June 2012. The study monitored consecutive neonates born to mothers from one Arab Muslim tribe that was assumed to have a low prevalence of G6PD-deficiency. Neonates that satisfied the following criteria were included: full-term birth (37 weeks); no admission to the special care nursery; no phototherapy treatment; negative direct antiglobulin test; and fathers of female neonates were from the same mothers’ tribe. The G6PD activity (Units/gram Hemoglobin) was measured spectrophotometrically by an automated kit. This study used statistical analyses endorsed by IFCC and CLSI for reference interval estimation. The 2.5th percentiles and the corresponding 95% confidence intervals (CI) were estimated as LRLs, both in presence and absence of outliers.Results207 males and 188 females term neonates who had cord blood quantitative G6PD testing met the inclusion criteria. Method of Horn detected 20 G6PD values as outliers (8 males and 12 females). Distributions of quantitative cord G6PD values exhibited a normal distribution in absence of the outliers only. The Harris-Boyd method and proportion criteria revealed that combined gender LRLs were reliable. The combined bootstrap LRL in presence of the outliers was 10.0 (95% CI: 7.5-10.7) and the combined parametric LRL in absence of the outliers was 11.0 (95% CI: 10.5-11.3).ConclusionThese results contribute to the LRL of quantitative cord G6PD detection in full-term neonates. They are transferable to another laboratory when pre-analytical factors and testing methods are comparable and the IFCC-CLSI requirements of transference are satisfied. We are suggesting using estimated LRL in absence of the outliers as mislabeling G6PD-deficient neonates as normal is intolerable whereas mislabeling G6PD-normal neonates as deficient is tolerable.

Androgen Profiling by Liquid Chromatography–Tandem Mass Spectrometry (LC-MS/MS) in Healthy Normal-Weight Ovulatory and Anovulatory Late Adolescent and Young Women

Physiological transient imbalance typical of adolescence needs to be distinguished from hyperandrogenism-related dysfunction. The accurate determination of circulating androgens is the best indicator of hyperandrogenism. However, reliable reference intervals for adolescent and young women are not available. The aim of the study was to define androgen reference intervals in young women and to analyze the impact of the menstrual phase and ovulation efficiency over the androgen profile as assessed by reliable liquid chromatography-tandem mass spectrometry (LC-MS/MS) technique. Female high school students aged 16-19 years were included in the study. The study was performed on reference subjects properly selected among an unbiased population. Normal-weight, drug and disease free, eumenorrheic females with no signs of hyperandrogenism were included. The steroid hormone profile was determined by a validated in-house LC-MS/MS method. A statistical estimation of overall and menstrual phase-specific reference intervals was performed. A subgroup of anovulatory females was identified based on progesterone circulating levels. The impact of ovulation efficiency over hormonal profile was analyzed. A total of 159 females satisfied healthy criteria. Androgen levels did not vary according to menstrual phase, but a significantly higher upper reference limit was found for T in the luteal phase compared to the follicular phase. Higher T and androstenedione levels were observed in anovulatory compared to ovulatory females, paralleled by higher LH and FSH and lower 17-hydroxyprogesterone and 17β-estradiol levels. This is the first study providing LC-MS/MS-based, menstrual phase-specific reference intervals for the circulating androgen profile in young females. We identified a subgroup of anovulatory healthy females characterized by androgen imbalance.

Elaboração e validação de intervalos de referência longitudinais de peso fetal com uma amostra da população brasileira

To elaborate models for the estimation of fetal weight and longitudinal reference intervals of estimated fetal weight (EFW) using a sample of the Brazilian population. Prospective observational study. Two groups of patients were evaluated: Group EFW (estimation of fetal weight): to elaborate (EFW-El) and validate (EFW-Val) a model for the prediction of fetal weight; Group LRI (longitudinal reference intervals): To elaborate (LRI-El) and validate (LRF-Val) conditional (longitudinal) percentiles of EFW. Polynomial regression analysis was applied to the data from subgroup EFW-El to elaborate a model for the estimation of fetal weight. The performance of this model was compared to those of previously published formulas. Linear mixed models were used for the elaboration of longitudinal reference intervals of EFW using data from subgroup LRI-El. Data obtained from subgroup LRI-Val were used to validate these intervals. Group EFW consisted of 458 patients (EFW-El: 367; EFW-Val: 91) and Group LRI consisted of 315 patients (LRI-El: 265; LRI-Val: 50). The model obtained for EFW was: EFW=-8.277+2.146xBPDxACxFL-2.449xFLxBPD². The performances of other models were significantly worse than those obtained with our formula. Equations for the prediction of conditional percentiles of EFW were derived from the longitudinal observation of patients of subgroup LRI-El and validated with data from subgroup LRI-Val. We described a method for customization of longitudinal reference intervals of EFW obtained using formulas generated from a sample of the Brazilian population.