Comparison of three congruent patient-specific cell types for the modelling of a human genetic Schwann-cell disorder.

Patient-specific human-induced pluripotent stem cells (hiPSCs) hold great promise for the modelling of genetic disorders. However, these cells display wide intra- and interindividual variations in gene expression, which makes distinguishing true-positive and false-positive phenotypes challenging. Data from hiPSC phenotypes and human embryonic stem cells (hESCs) harbouring the same disease mutation are also lacking. Here, we report a comparison of the molecular, cellular and functional characteristics of three congruent patient-specific cell types-hiPSCs, hESCs and direct-lineage-converted cells-derived from currently available differentiation and direct-reprogramming technologies for use in the modelling of Charcot-Marie-Tooth 1A, a human genetic Schwann-cell disorder featuring a 1.4 Mb chromosomal duplication. We find that the chemokines C-X-C motif ligand chemokine-1 (CXCL1) and macrophage chemoattractant protein-1 (MCP1) are commonly upregulated in all three congruent models and in clinical patient samples. The development of congruent models of a single genetic disease using somatic cells from a common patient will facilitate the search for convergent phenotypes.

Personalized prediction of first-cycle in vitro fertilization success.

OBJECTIVE: To test whether the probability of having a live birth (LB) with the first IVF cycle (C1) can be predicted and personalized for patients in diverse environments. DESIGN: Retrospective validation of multicenter prediction model. SETTING: Three university-affiliated outpatient IVF clinics located in different countries. PATIENT(S): Using primary models aggregated from >13,000 C1s, we applied the boosted tree method to train a preIVF-diversity model (PreIVF-D) with 1,061 C1s from 2008 to 2009, and validated predicted LB probabilities with an independent dataset comprising 1,058 C1s from 2008 to 2009. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Predictive power, reclassification, receiver operator characteristic analysis, calibration, dynamic range. RESULT(S): Overall, with PreIVF-D, 86% of cases had significantly different LB probabilities compared with age control, and more than one-half had higher LB probabilities. Specifically, 42% of patients could have been identified by PreIVF-D to have a personalized predicted success rate >45%, whereas an age-control model could not differentiate them from others. Furthermore, PreIVF-D showed improved predictive power, with 36% improved log-likelihood (or 9.0-fold by log-scale; >1,000-fold linear scale), and prediction errors for subgroups ranged from 0.9% to 3.7%. CONCLUSION(S): Validated prediction of personalized LB probabilities from diverse multiple sources identify excellent prognoses in more than one-half of patients.

High frequency of discordance between antimüllerian hormone and follicle-stimulating hormone levels in serum from estradiol-confirmed days 2 to 4 of the menstrual cycle from 5,354 women in U.S. fertility centers.

OBJECTIVE: To determine the frequency of clinical discordance between antimüllerian hormone (AMH, ng/mL) and follicle-stimulating hormone (FSH, IU/L) by use of cut points defined by response to controlled ovarian stimulation in the same serum samples drawn on estradiol-confirmed, menstrual cycle days 2 to 4. DESIGN: Retrospective analysis. SETTING: Fertility centers in 30 U.S. states and a single reference laboratory with uniform testing protocols. PATIENT(S): 5,354 women, 20 to 45 years of age. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Frequency of discordance between serum AMH and FSH values. RESULT(S): Of the 5,354 women tested, 1 in 5 had discordant AMH and FSH values defined as AMH <0.8 (concerning) with FSH <10 (reassuring) or AMH ≥ 0.8 (reassuring) with FSH ≥ 10 (concerning). Of the women with reassuring FSH values (n = 4,469), the concerning AMH values were found in 1 in 5 women in a highly age-dependent fashion, ranging from 1 in 11 women under 35 years of age to 1 in 3 women above 40 years of age. On the other hand, of the women with reassuring AMH values (n = 3,742), 1 in 18 had concerning FSH values, a frequency that did not vary in a statistically significant fashion by age. CONCLUSION(S): Clinical discordance in serum AMH and FSH values was frequent and age dependent using common clinical cut points, a large patient population, one reference laboratory, and uniform testing methodology. This conclusion is generalizable to women undergoing fertility evaluation, although AMH testing has not been standardized among laboratories, and the cut points presented are specific to the laboratory in this study.

Predicting personalized multiple birth risks after in vitro fertilization-double embryo transfer.

OBJECTIVE: To report and evaluate the performance and utility of an approach to predicting IVF-double embryo transfer (DET) multiple birth risks that is evidence-based, clinic-specific, and considers each patient's clinical profile. DESIGN: Retrospective prediction modeling. SETTING: An outpatient university-affiliated IVF clinic. PATIENT(S): We used boosted tree methods to analyze 2,413 independent IVF-DET treatment cycles that resulted in live births. The IVF cycles were retrieved from a database that comprised more than 33,000 IVF cycles. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The performance of this prediction model, MBP-BIVF, was validated by an independent data set, to evaluate predictive power, discrimination, dynamic range, and reclassification. RESULT(S): Multiple birth probabilities ranging from 11.8% to 54.8% were predicted by the model and were significantly different from control predictions in more than half of the patients. The prediction model showed an improvement of 146% in predictive power and 16.0% in discrimination over control. The population standard error was 1.8%. CONCLUSION(S): We showed that IVF patients have inherently different risks of multiple birth, even when DET is specified, and this risk can be predicted before ET. The use of clinic-specific prediction models provides an evidence-based and personalized method to counsel patients.

Techniques for removal of the Essure hysteroscopic tubal occlusion device.

OBJECTIVE: To present two case reports of techniques for removal of the Essure (Conceptus, Inc., Mountain View, CA) hysteroscopic tubal occlusion device. DESIGN: Case report. SETTING: University-affiliated teaching hospital. PATIENT(S): Two women requesting removal of Essure devices because of persistent pelvic pain up to 6 weeks after placement. INTERVENTION(S): Hysteroscopic and laparoscopic removal of the Essure microinserts. No institutional review board approval was obtained because the procedures were not part of a study protocol. MAIN OUTCOME MEASURE(S): Effective removal of the Essure device and resolution of pelvic pain symptoms. RESULT(S): Successful removal of the device was achieved in both patients. In one case, the procedure was performed entirely by hysteroscopy. In the other case, a laparoscopic approach was required because of a lack of visualization of the device. Pain symptoms resolved within 2 weeks of removal in both patients. CONCLUSION(S): These are the first reported cases of successful removal of the Essure tubal occlusion devices up to 6 weeks after placement. This procedure can be safely performed with the use of hysteroscopy if the inserts are clearly visualized. Laparoscopy is an alternative when the device is completely within the fallopian tube. Further study is needed to assess the functionality of the tube after the procedure, as well as feasibility of removal beyond 6 weeks.