Development of a Third Trimester Contingent Prognostic Prediction Scheme for Suspected Early-Onset Pre-Eclampsia.

INTRODUCTION: Short-term prediction of pre-eclampsia (PE) using soluble FMS-like tyrosine kinase-1 (sFlt-1)/ placental growth factor (PlGF) ratio has high false-positive rate. Therefore, we developed a prognostic prediction tool that predicts early-onset PE leading to delivery within 1 week on pregnancies with an sFlt-1/PlGF ratio above 38 and compared it with an analogous model based on sFlt-1/PlGF ratio and with the 655 sFlt-1/PlGF ratio cutoff. METHODS: Cohort study of 363 singleton pregnancies with clinical suspicion of PE before 34 weeks of gestation, allowing repeated assessments (522). 213 samples with an sFlt-1/PlGF ratio above 38 were assessed to construct and identify the best-fit linear mixed model. N-terminal pro-B-type natriuretic peptide (NT-proBNP), sFlt-1 MoM, PlGF MoM, and sFlt-1/PlGF ratio combined with gestational age (GA) were assessed. RESULTS: None of the pregnancies with an sFlt-1/PlGF ratio of 38 or below developed early-onset PE (309 samples from 240 pregnancies). Conversely, 47 women of 213 assessments (22.1%) with an sFlt-1/PlGF ratio above 38 developed the assessed outcome. The selected model included sFlt-1 MoM, NT-proBNP, and GA. Differences in area under the curve were observed between the selected model and the GA + sFlt-1/PlGF model (p = 0.04). At an sFlt-1/PlGF ratio cutoff of 655, detection rate was 31.9% (15/47), while the selected model detection was 55.3% (26/47) (p = 0.008). DISCUSSION: Considering repeated assessments, the sFlt-1/PlGF ratio of 38 or below adequately ruled out early-onset PE, leading to delivery within 1 week. However, when sFlt-1/PlGF ratio is above 38, the prediction tool derived from linear mixed model based on GA, NT-proBNP, and sFlt-1 MoM, provided a better prognosis prediction than the sFlt-1/PlGF ratio.

A likelihood ratio approach for identifying three-quarter siblings in genetic databases.

The detection of family relationships in genetic databases is of interest in various scientific disciplines such as genetic epidemiology, population and conservation genetics, forensic science, and genealogical research. Nowadays, screening genetic databases for related individuals forms an important aspect of standard quality control procedures. Relatedness research is usually based on an allele sharing analysis of identity by state (IBS) or identity by descent (IBD) alleles. Existing IBS/IBD methods mainly aim to identify first-degree relationships (parent-offspring or full siblings) and second degree (half-siblings, avuncular, or grandparent-grandchild) pairs. Little attention has been paid to the detection of in-between first and second-degree relationships such as three-quarter siblings (3/4S) who share fewer alleles than first-degree relationships but more alleles than second-degree relationships. With the progressively increasing sample sizes used in genetic research, it becomes more likely that such relationships are present in the database under study. In this paper, we extend existing likelihood ratio (LR) methodology to accurately infer the existence of 3/4S, distinguishing them from full siblings and second-degree relatives. We use bootstrap confidence intervals to express uncertainty in the LRs. Our proposal accounts for linkage disequilibrium (LD) by using marker pruning, and we validate our methodology with a pedigree-based simulation study accounting for both LD and recombination. An empirical genome-wide array data set from the GCAT Genomes for Life cohort project is used to illustrate the method.

A Log-Ratio Biplot Approach for Exploring Genetic Relatedness Based on Identity by State.

The detection of cryptic relatedness in large population-based cohorts is of great importance in genome research. The usual approach for detecting closely related individuals is to plot allele sharing statistics, based on identity-by-state or identity-by-descent, in a two-dimensional scatterplot. This approach ignores that allele sharing data across individuals has in reality a higher dimensionality, and neither regards the compositional nature of the underlying counts of shared genotypes. In this paper we develop biplot methodology based on log-ratio principal component analysis that overcomes these restrictions. This leads to entirely new graphics that are essentially useful for exploring relatedness in genetic databases from homogeneous populations. The proposed method can be applied in an iterative manner, acting as a looking glass for more remote relationships that are harder to classify. Datasets from the 1,000 Genomes Project and the Genomes For Life-GCAT Project are used to illustrate the proposed method. The discriminatory power of the log-ratio biplot approach is compared with the classical plots in a simulation study. In a non-inbred homogeneous population the classification rate of the log-ratio principal component approach outperforms the classical graphics across the whole allele frequency spectrum, using only identity by state. In these circumstances, simulations show that with 35,000 independent bi-allelic variants, log-ratio principal component analysis, combined with discriminant analysis, can correctly classify relationships up to and including the fourth degree.

Cumulative sum plots and retrospective parameters in first-trimester ductus venosus quality assurance.

OBJECTIVE: This study aimed to evaluate the application of two quality assurance methods to the ductus venosus pulsatility index (DVPI), as a first-trimester aneuploidy marker, including retrospective assessment of distribution parameters and cumulative sum (CUSUM) plots. METHODS: The DVPI was measured in 14 444 singleton fetuses at 11+0 to 13+6 weeks in two Fetal Medicine centers during a 4-year period. Sonologist-specific quality assurance distribution parameters, previously described for nuchal translucency, were assessed: the median multiples of the median (MoM), the logarithmic standard deviation of DVPI MoMs and the weekly DVPI percent decrease. Quality assurance results were compared between median MoMs and MoM-based CUSUM plots. RESULTS: When sonologist-specific DVPI distribution parameters were retrospectively applied for quality assurance, a 1.0 median MoM, a 0.1 median logarithmic standard deviation and a 3.4 median weekly DVPI drop percentage were observed. CUSUM plots showed good agreement with 0.9-1.1 MoMs range for median MoM, in the assessment of sonologist-specific performances. CONCLUSION: Retrospective and prospective DVPI quality assurance methods appear to be applicable to DVPI at 11+0 to 13+6 weeks. Its use should be encouraged if DVPI is to be added to first-trimester Down syndrome or cardiac defects screening.

Updated reference ranges for the ductus venosus pulsatility index at 11-13 weeks.

OBJECTIVE: To update the reference ranges for the ductus venosus pulsatility index (DVPI) at 11+0 to 13+6 gestational weeks. METHODS: DVPI was calculated in 14,444 singleton fetuses at 11+0 to 13+6 weeks in two Fetal Medicine Centers, during a 4-year period. Using previously described medians, DVPI evolution was assessed both over the study period on a yearly basis and over gestation, grouping fetuses according to 5-mm crown-rump length (CRL) ranges. Weighted DVPI medians, the 5th and 95th percentiles and distribution parameters for unaffected and trisomy 21 fetuses were newly calculated. RESULTS: A significant DVPI multiple of the median decrease was observed over both the study period (p < 0.01) and over gestation (p < 0.01) using previous medians, in the two centers. Newly calculated weighted medians were lower than those previously described, decreasing with CRL. Distribution parameters calculated using the new medians were different from those previously described. CONCLUSION: DVPI reference ranges were lower than those previously reported and decreased with CRL. Updated medians and distribution parameters should be considered to include the DVPI as a Gaussian marker in trisomy 21 screening and for quality control purposes.

Usefulness of prebiopsy multifunctional and morphologic MRI combined with free-to-total prostate-specific antigen ratio in the detection of prostate cancer.

OBJECTIVE: The purpose of the study was to assess the predictive value for prostate cancer of MRI using morphologic (T2-weighted imaging [T2WI]) and functional (MR spectroscopy [MRS], diffusion-weighted imaging [DWI], and dynamic contrast-enhanced [DCE] MRI) sequences and the free-to-total prostate-specific antigen (PSA) ratio, alone and combined. MATERIALS AND METHODS: This retrospective study included 70 patients (PSA level, > 4 ng/mL; free-to-total PSA ratio, < 20%) who underwent endorectal 1.5-T MRI before biopsy. We graded the likelihood of cancer on a 5-point scale. Imaging data were compared with histologic results on biopsy or prostatectomy. Accuracies were estimated from the area under receiver operating characteristic using the hemiprostate as the unit of analysis. A p value less than 0.05 denoted statistical significance. RESULTS: The model combining all variables was more accurate than each variable alone (95.2% vs 73.5% for T2WI, 76.0% for MRS, 81.8% for DWI, 75.6% for DCE-MRI, and 78.8% for free-to-total PSA ratio). The complete model had accuracy similar to that of combining two imaging variables with free-to-total PSA ratio, especially free-to-total PSA ratio, T2WI, and DWI (94.0%); and free-to-total PSA ratio, DWI, and MRS (93.8%); with negative predictive values of 91.0% and 89.5%, respectively. The best models combining two imaging variables (MRS and DWI, 85.8%; T2WI and DWI, 84.8%) had accuracy that was similar to that of the combination of all imaging variables (87.3%) and higher than that of the best individual imaging variable (DWI, 81.8%), but lower than that of the complete model. CONCLUSION: The combination of at least one functional technique with free-to-total PSA ratio is more accurate than combining only imaging variables in cancer detection. The use of more than two imaging variables does not increase the detection rate. Functional MRI has the potential to help avoid a large number of negative biopsies.

Utilidad de la resonancia magnética con espectroscopia en el diagnóstico del cáncer de próstata / Use of magnetic resonance spectroscopy in diagnosing prostate cancer

Introducción: El diagnóstico del cáncer de próstata (CaP) está basado inicialmente en una combinación del valor del antígeno prostático específico (PSA), el tacto rectal (TR) y los hallazgos de la ecografía transrectal de la próstata (ETR). La ETR ofrece la posibilidad de realizar biopsias aleatorias de la glándula prostática, que a menudo acaban siendo múltiples biopsias repetidas negativas en pacientes con elevación persistente del PSA, debido a la baja especificidad de este marcador. La resonancia magnética (RM) endorrectal es actualmente el mejor método de imagen para la detección del CaP. La espectroscopia por RM endorrectal (RMS) es una técnica no invasiva que complementa el diagnóstico del CaP mediante la detección de metabolitos intracelulares a nivel de la próstata, tales como la colina y el citrato. La RMS combinada con la RM endorrectal mejora de forma significativa la evaluación de la localización del CaP. Método: Se realizó un estudio para determinar la eficacia de la RMS en la detección precoz del CaP en pacientes con elevación del PSA, alteración del TR o ambos, candidatos a biopsia transrectal de próstata. Seleccionamos 51 pacientes entre 50-65 años con PSA entre 4-15 ng/ml con o sin alteración del TR, que debían ser sometidos a biopsia TR de próstata. La sospecha de tumor según la RM y RMS fue clasificada en una escala de 1-4, en la que 1 equivale a normal y 4 a cáncer. Comparamos 306 imágenes (6 por paciente) de RM y 306 curvas espectroscópicas con los valores de PSAt, índice de PSAt/PSAl, TR y la AP de cada uno de los sextantes. Resultados: Diagnosticamos CaP en 23 de 45 pacientes (45%) y en 78 de 306 sextantes (25%). El cociente CC/Ci fue significativamente superior en los pacientes con CaP (1.05 ± 0.41) en comparación con los pacientes en los que no se demostró CaP (0.51 ± 0.21). El índice PSAl/PSAt fue también significativamente inferior en los pacientes con CaP (11.35%) respecto de los pacientes sin CaP (16.55%)...

Utilidad de la resonancia magnética con espectroscopia en el diagnóstico del cáncer de próstata / Use of magnetic resonance spectroscopy in diagnosing prostate cancer

Introducción: El diagnóstico del cáncer de próstata (CaP) está basado inicialmente en una combinación del valor del antígeno prostático específico (PSA), el tacto rectal (TR) y los hallazgos de la ecografía transrectal de la próstata (ETR). La ETR ofrece la posibilidad de realizar biopsias aleatorias de la glándula prostática, que a menudo acaban siendo múltiples biopsias repetidas negativas en pacientes con elevación persistente del PSA, debido a la baja especificidad de este marcador. La resonancia magnética (RM) endorrectal es actualmente el mejor método de imagen para la detección del CaP. La espectroscopia por RM endorrectal (RMS) es una técnica no invasiva que complementa el diagnóstico del CaP mediante la detección de metabolitos intracelulares a nivel de la próstata, tales como la colina y el citrato. La RMS combinada con la RM endorrectal mejora de forma significativa la evaluación de la localización del CaP. Método: Se realizó un estudio para determinar la eficacia de la RMS en la detección precoz del CaP en pacientes con elevación del PSA, alteración del TR o ambos, candidatos a biopsia transrectal de próstata. Seleccionamos 51 pacientes entre 50-65 años con PSA entre 4-15 ng/ml con o sin alteración del TR, que debían ser sometidos a biopsia TR de próstata. La sospecha de tumor según la RM y RMS fue clasificada en una escala de 1-4, en la que 1 equivale a normal y 4 a cáncer. Comparamos 306 imágenes (6 por paciente) de RM y 306 curvas espectroscópicas con los valores de PSAt, índice de PSAt/PSAl, TR y la AP de cada uno de los sextantes. Resultados: Diagnosticamos CaP en 23 de 45 pacientes (45%) y en 78 de 306 sextantes (25%). El cociente CC/Ci fue significativamente superior en los pacientes con CaP (1.05 ± 0.41) en comparación con los pacientes en los que no se demostró CaP (0.51 ± 0.21). El índice PSAl/PSAt fue también significativamente inferior en los pacientes con CaP (11.35%) respecto de los pacientes sin CaP (16.55%)...(AU)

Peripheral zone prostate cancer in patients with elevated PSA levels and low free-to-total PSA ratio: detection with MR imaging and MR spectroscopy.

PURPOSE: To retrospectively assess the value of endorectal magnetic resonance (MR) imaging and MR spectroscopy combined with the free-to-total prostate-specific antigen (PSA) ratio for detecting prostate cancer in men with elevated PSA levels. MATERIALS AND METHODS: The institutional review board approved the study, and all patients provided informed written consent. Endorectal MR imaging and MR spectroscopy were performed in 54 patients with PSA levels greater than 3 ng/mL but less than 15 ng/mL and free-to-total PSA ratio of less than 20%, followed by sextant biopsy in the peripheral zone. For each patient, MR imaging and MR spectroscopic findings, PSA level, and free-to-total PSA ratio were analyzed and compared with biopsy results and/or histopathologic tumor maps with regard to a sextant-modified distribution. The likelihood of cancer in each sextant according to MR and MR spectroscopic findings was graded independently on a scale of 1 (benign) to 5 (malignant). Detection accuracy and a multivariate logistic regression analysis were used to determine the most accurate combination of imaging, and clinical tests were used to detect prostate cancer according to the area under the receiver operating characteristic curve (AUC). RESULTS: The model incorporating MR imaging, MR spectroscopy, and free-to-total PSA ratio (AUC = 97.5%) was significantly more accurate in predicting prostate cancer than models using MR imaging alone (AUC = 85.1%; P = .007), MR spectroscopy alone (AUC = 87.2%; P = .041), or MR imaging and free-to-total PSA ratio combined (AUC = 90.8%; P = .038). CONCLUSION: MR and MR spectroscopy combined with free-to-total PSA ratio improves the predictive value for prostate cancer detection.

Diagnóstico del cáncer de próstata mediante espectroscopia de resonancia magnética endorectal / The diagnosis of prostate cancer by endorectal MR spectroscopy

OBJETIVO: La espectroscopia de resonanciamagnética endorectal (RMS) es una nueva técnica de imagen que permite realizar una evaluación más precisa y fiable de la localización y estadiaje del cáncerde próstata (CaP) que el estudio morfológico aisladoque ofrece la resonancia magnética endorectal sola. La combinación de la RM endorectal y la RMS ofrece la posibilidad de realizar un estudio morfológico y metabólicosimultáneo, que sin duda consigue mejoras en la detección del CaP. Además, el perfeccionamiento técnicointroducido recientemente en el estudio espectroscópicode la próstata ha permitido también aumentar la fiabilidad en la detección del CaP.MÉTODOS/RESULTADOS: Presentamos en este artículo las ventajas que esta técnica ofrece tanto para la deteccióndel CaP en pacientes con riesgo de sufrir esta neoplasia, como también su utilidad en pacientes con biopsias previas negativas y progresiva elevación del PSA. Presenta también ventajas en el estudio de las recidivasbioquímicas del PSA en pacientes tratados previamente,y en el estudio de la glándula central prostática. Comentaremos también la posibilidad de utilizarla en el estadiaje del CaP. Nuestro grupo está actualmente trabajandocon la RMS en la detección del CaP, en colaboracióncon la Agencia de Evaluación de Tecnología para la Investigación Médica (AATRM), y presentamos algunos resultados obtenidos mediante la utilización de esta técnica.CONCLUSIONES: La RMS es un método poco invasivoque ofrece la capacidad de detectar el CaP en la glándula periférica, con mayor fiabilidad que la RM endorectal sola, en pacientes seleccionados. Es una muy buena herramienta para el estudio de la glándula central en la que la detección de neoplasias resulta muy difícil por métodos puramente morfológicos. Por tanto, la RMS permite evaluar las alteraciones metabólicas en toda la glándula y aumentar así la fiabilidad en la deteccióndel CaP, tanto en la glándula central como en la periférica

OBJECTIVES: The endorectal MR spectroscopic imaging (MRS) is a new imaging technique that allows a more accurate and reliable evaluation for the localization and staging of prostate cancer(PCa) than the solemorphological study offered by endorectal MR alone. The combination of endorectal MRI and MRS allows a simultaneous morphologic and metabolic study thatimproves the detection of PCa. Moreover, the technical improvements recently introduced in the spectroscopic study of the prostate have led to an increase of reliability in the detection of PCa.METHODS AND RESULTS: We present in this article the advantages this technique offers in the detection of PCa in patients at high risk, as well as in patients with progressive PSA rising and previous negative biopsies. It also seems to be useful in the study of biochemical recurrences of PSA in previously treated patients, and for the study of the central gland. We comment, as well, the chance to use this tool in the staging of PCa. Our group is actually working with MRS in the detection of PCa, in collaboration with AATRM (Agency of Evaluation ofmedical technology for medical research) and wepresent some recent results in the use of this technique.CONCLUSIONS: MRS is a non-invasive method that allows the detection of PCa in the peripheral gland with a greater reliability than endorectal MRI alone, in selectyed patients. It is also a good technique for the study of the central gland, in which the detection of PCa is difficult by morphological methods. So, RMS allows the evaluation of metabolic disorders in the whole prostatic gland and improves the overall accuracy in the detection of PCa, either in the central or peripheral gland

[Localization of prostate cancer within the central gland by endorectal MR spectroscopic imaging]. / Localización del cáncer de próstata en la glándula central mediante espectroscopia de resonancia magnética endorectal.

OBJECTIVES: The endorectal MR spectroscopic imaging is a new imaging test which allows more accurate and reliable localization and staging of prostate cancer than simple endorectal MRI. The combination of spectroscopic MR and MRI has recently achieved technical improvements that increased reliability in the detection of prostate cancer. Our group is now working in the detection of prostate cancer with the spectroscopic MR, in co-operation with the Agency for the Evaluation of Technology for Medical Research (Agencia de Evaluación de Tecnología para la Investigación Médica-AATRM); although we are waiting for definitive results, we can advance that this technique may be used as a good alternative for localization of prostate cancer in patients with previous negative biopsies in whom the suspicion of prostate cancer persists. METHODS: We present a series of 5 patients under control for permanent elevation of PSA with previous negative biopsies. We were performing ultrasound guided sextant biopsies every 6 months, after blood test for PSA. Endorectal MRI and spectroscopic MRI were performed to try to localize the prostate cancer so diminishing the number of biopsies. RESULTS: All patients in the series had a low intensity lesion within the normal low intensity of the central gland, with an obvious spectroscopic metabolic abnormality suggesting the existence of prostate cancer, as it was then demonstrated by biopsy. CONCLUSIONS: The endorectal MR spectroscopic imaging is a non invasive method which offers the ability to detect prostate cancer within the central gland with a higher reliability in selected patients. The central gland is an area in which prostate cancer is less commonly localized, but it often shows the same signal intensity than hyperplastic tissue, so that it is difficult to be detected by purely morphological methods. Endorectal MR spectroscopic imaging allows evaluating the metabolic disturbances in the whole gland, increasing the reliability of detection of prostate cancer both in the central and peripherical glands.

Localización del cáncer de próstata en la glándula central mediante espectroscopia de resonancia magnética endorectal / Localization of prostate cancer within the central gland by endorectal MR spectroscopic imaging

OBJETIVO: La espectroscopia de resonanciamagnética endorectal (E-RME) es una nueva técnicade imagen que permite una evaluación más acuraday fiable de la localización y estadiaje del cáncerde próstata (CaP) que la resonancia magnética endorectalsola. La combinación de la RME y la E-RME haconseguido recientemente mejorías técnicas que hanpermitido aumentar la fiabilidad en la detección delCaP. Nuestro grupo está actualmente trabajando con laE-RME en la detección del CaP, en colaboración con laAgencia de Evaluación de Tecnología para laInvestigación Médica (AATRM), y en espera de resultadosdefinitivos podemos avanzar que ésta técnicapuede ser utilizada como una buena alternativa en lalocalización de CaP en pacientes con biopsias previasnegativas pero en quienes persiste la sospecha de CaP.MÉTODOS: Presentamos aquí una serie de 5 casos clínicosde pacientes controlados por elevación persistentedel PSA y biopsias previas negativas. Realizamosbiopsias por sextantes mediante ecografía transrectal aintervalos de 6 meses, después de determinar los valoresde PSA. La RME y E-RME se realizó para intentarlocalizar el CaP y de este modo intentar minimizar elnúmero de biopsias.RESULTADOS: Todos los pacientes en esta serie presentaronuna lesión de baja intensidad localizada en lahipointensidad normal de la glándula central, pero conuna clara alteración metabólica en la espectroscopiaque sugería la existencia de un CaP, tal como sedemostró posteriormente por biopsia.CONCLUSIONES: La E-RME es un método poco invasivoque ofrece la capacidad de detectar el CaP en laglándula central con mayor fiabilidad en pacientesseleccionados. La glándula central es una zona en laque el CaP se localiza con menor frecuencia, pero amenudo adopta la misma intensidad de señal que eltejido hiperplásico, y por tanto, resulta difícil de detectarpor métodos puramente morfológicos. La E-RME permiteevaluar las alteraciones metabólicas en toda laglándula y aumentar así la fiabilidad en la deteccióndel CaP, tanto en la glándula central como en la periférica

OBJECTIVES: The endorectal MRspectroscopic imaging is a new imaging test whichallows more accurate and reliable localization andstaging of prostate cancer than simple endorectal MRI.The combination of spectroscopic MR and MRI hasrecently achieved technical improvements that increasedreliability in the detection of prostate cancer. Our groupis now working in the detection of prostate cancer withthe spectroscopic MR, in co-operation with the Agencyfor the Evaluation of Technology for Medical Research(Agencia de Evaluación de Tecnología para laInvestigación Médica-AATRM); although we are waitingfor definitive results, we can advance that this techniquemay be used as a good alternative for localization ofprostate cancer in patients with previous negative biopsiesin whom the suspicion of prostate cancer persists.METHODS: We present a series of 5 patients undercontrol for permanent elevation of PSA with previousnegative biopsies. We were performing ultrasound guidedsextant biopsies every 6 months, after blood test forPSA. Endorectal MRI and spectroscopic MRI wereperformed to try to localize the prostate cancer sodiminishing the number of biopsies.RESULTS: All patients in the series had a low intensitylesion within the normal low intensity of the centralgland, with an obvious spectroscopic metabolicabnormality suggesting the existence of prostate cancer,as it was then demonstrated by biopsy.CONCLUSIONS: The endorectal MR spectroscopicimaging is a non invasive method which offers theability to detect prostate cancer within the central glandwith a higher reliability in selected patients. The centralgland is an area in which prostate cancer is lesscommonly localized, but it often shows the same signalintensity than hyperplastic tissue, so that it is difficult tobe detected by purely morphological methods.Endorectal MR spectroscopic imaging allows evaluatingthe metabolic disturbances in the whole gland, increasingthe reliability of detection of prostate cancer both in thecentral and peripherical glands