Geralyn Lambert-Messerlian

Background: Currently, there are no accurate clinical biomarkers for the management of patients diagnosed with endometrial cancer. The biomarker HE4 is often overexpressed and found to be elevated in the serum of patients with endometrial cancers. Objective: The objective of this trial was to assess the utility of HE4 as a biomarker for monitoring patients with endometrial cancer.Methods: This was an IRB-approved trial utilizing residual serial serum samples from patients diagnosed with endometrial cancer. Clinical status was determined by a combination of physician assessment, physical exam, serum CA125 levels, and imaging. Two separate analyses were performed to assess changes in HE4 serum levels. The first method used a change of 25% over that of the previous serum HE4 value, and the second analysis employed a velocity of change calculation of serum HE4 levels over time.Results: A total of 92 patients providing 799 serum samples were identified for analysis. Using a ≥25.0% increase of serum HE4 levels as an indicator of disease recurrence or progression, HE4 had an accuracy of 81.9% and a negative predictive value of 91.4%. The velocity of change analysis an accuracy of 85.4% with a negative predictive value of 86.7%.Conclusion: HE4 is highly accurate for detecting disease recurrence or progression and is a valuable clinical tool for monitoring patients with endometrial cancer.

Background: Serum AMH levels in adult women are part of the diagnostic criteria for polycystic ovary syndrome (PCOS), a condition with marked infertility and metabolic risks. Yet, little is known about AMH levels among women from ethnic minority populations, especially its associations with age and obesity. The objective is to describe the association of age and serum anti-mullerian hormone (AMH) among Samoan women, provide age specific AMH reference levels, and examine the associations of AMH with adiposity and reproductive factors. Methods: A cross-sectional, retrospective study of a representative community-based sample from Samoa was conducted. 670 women with no known reproductive disorders, reproductive surgeries, or hormonal contraceptive use, age 25–51 years, were included. Adiposity was assessed by body mass index (BMI) using Polynesian-specific criteria for obesity. Serum AMH was determined by enzyme-linked immunosorbent assay. Serum total testosterone and sex hormone binding globulin were measured, and the free androgen index was calculated. Hormonal contraceptive use, menstrual regularity, and tobacco use were assessed by questionnaire. PCOS prevalence was estimated using current guidelines. Results: Despite a high prevalence of obesity and overweight in Samoan women, serum AMH and its age related decline were similar to those reported in other populations. AMH was negatively associated with age. AMH decline with age in Samoan women is best described by a cubic model. AMH was not associated with BMI or insulin resistance. PCOS prevalence was estimated at 3.4–5.1%. Conclusion: This study was the first to construct an age specific AMH reference range for Samoan women. PCOS prevalence appears low, supporting other published studies that have demonstrated a complex relationship between adiposity and reproductive health in Samoan women. Clinical trial number: Not applicable.

Study question: Can a genome-wide association study (GWAS) and transcriptome-wide association study (TWAS) help identify genetic variation or genes associated with circulating anti-Müllerian hormone (AMH) levels in Samoan women? Summary answer: We identified eleven genome-wide suggestive loci (strongest association signal in ARID3A 19-946163-G-C [ p = 2.32 × 10⁻⁷]) and seven transcriptome-wide significant genes ( GINS2, SENP3, USP7, TUSC3, MAFA, METTL4, NDFIP1 [all with a p < 2.50 × 10⁻⁶]) associated with circulating AMH levels in Samoan women. What is known already: Three prior GWASs of AMH levels identified eight loci in premenopausal women of European ancestry (AMH, MCM8, TEX41 , CHECK2, CDCA7 , EIF4EBP1, BMP4 and an uncharacterized non-coding RNA gene CTB-99A3.1 ), among which the MCM8 locus was shared among all three studies. Study design, size, duration: We included a sample of 1,185 women from two independently recruited samples: a family study ( n = 212; [age: 18 to 40 years]) recruited in 2002–03 from Samoa and American Samoa; and the Soifua Manuia Study ( n = 973; age: 25 to 51 years), a crosssectional population-based study recruited in 2010 from Samoa. Participants/materials, setting, methods: Serum AMH levels were measured using enzyme linked immunosorbent assays (ELISA). We performed GWASs in the two participant samples using a Cox mixed-effects model to account for AMH levels below detectable limits and adjusted for centered age, centered age², polity, and kinship via kinship matrix. The summary statistics were then meta-analyzed using a fixed-effect model. We annotated the variants with p < 1 × 10⁻⁵ and calculated posterior probability of causality for prioritization. We further annotated variants using FUMA and performed colocalization and transcriptome-wide association analysis. We also assessed whether any previously reported loci were replicated in our GWAS. Main results and the role of chance: We identified eleven novel genome-wide suggestive loci ( p < 1 × 10⁻⁵) associated with AMH levels and replicated EIF4EBP1, a previously reported AMH locus, in the GWAS. The lead variant in ARID3A , 19-946163-G-C is in high linkage disequilibrium ( r ² = 0.79) with the known age-at-menopause variant 19-950694-G-A. Nearby KISS1R is a biologically plausibility causal gene in the region; kisspeptin regulates ovarian follicle development and has been linked to AMH levels. Further investigation of the ARID3A locus is warranted. Limitations, reasons for caution: The main limitations of our study are the small sample size for a GWAS and the use of the transcription model trained on mostly European samples from the Genotype Tissue Expression (GTEx) project, which may have led to reduced power to detect genotype-expression associations. Our findings need to be validated in larger Polynesian cohorts. Wider implications of the findings: In addition to replicating one of the eight previously discovered AMH loci, we identified new suggestive associations. It is known that the inclusion of founder populations aids in the discovery of novel loci. These findings could enhance our understanding of AMH and AMH-related reproductive phenotypes (ovarian reserve, age at menopause, premature ovarian failure, and polycystic ovary syndrome) and help build a screening approach for women at risk for these phenotypes using genetically predicted AMH levels. Study funding/competing interest(s): This work was funded by NIH grants R01-HL093093 (PI: S.T.M.), R01-HL133040 (PI: R.L.M.), and T90-DE030853 (PI: C.S. Sfeir). Molecular data for the Trans-Omics in Precision Medicine (TOPMed) Program was supported by the National Heart, Lung and Blood Institute (NHLBI). The content is solely the responsibility of the authors and does not represent the official views of the National Institutes of Health.

Polycystic ovary syndrome (PCOS) is a recognized risk factor for the long-term health of women. PCOS is not only a challenge for reproductive health; it conveys lifelong risks for diabetes, dyslipidemia, hypertension, obstructive sleep apnea, endometrial cancer, and cardiovascular disease, among other morbidities ( 1). These increased risks persist even when controlling for high body mass index, a common feature of PCOS, and most apply across premenopausal and postmenopausal women. The health consequences are exacerbated by missed or late diagnoses, which are common. One provocative study showed that it often took more than 2 years and 3 different health care providers for women to receive a diagnosis of PCOS, regardless of residing in North America, Europe, or other parts of the world ( 2). An ongoing challenge in diagnosing PCOS and understanding its prevalence has been the lack of uniformity in clinical criteria ( 3). The National Institutes of Health (NIH), in 1990, was first to introduce diagnostic criteria for PCOS. A Rotterdam expert consensus (2003) then expanded the definition and later, the Androgen Excess and PCOS Society (2006) proposed a modification. Currently, the NIH evidence-based workshop (2012) recommends diagnosis by 2 of 3 criteria: ovulatory dysfunction, biochemical or clinical hyperandrogenism, and/or polycystic ovary morphology. Patients are categorized into 1 of 4 PCOS phenotypes based on the clinical findings.

Background: The integration of ChatGPT, a large language model (LLM) developed by OpenAI, into healthcare has sparked significant interest due to its potential to enhance patient care and medical education. With the increasing trend of patients accessing laboratory results online, there is a pressing need to evaluate the effectiveness of ChatGPT in providing accurate laboratory medicine information. Our study evaluates ChatGPT's effectiveness in addressing patient questions in this area, comparing its performance with that of medical professionals on social media. Methods: This study sourced patient questions and medical professional responses from Reddit and Quora, comparing them with responses generated by ChatGPT versions 3.5 and 4.0. Experienced laboratory medicine professionals evaluated the responses for quality and preference. Evaluation results were further analyzed using R software. Results: The study analyzed 49 questions, with evaluators reviewing responses from both medical professionals and ChatGPT. ChatGPT's responses were preferred by 75.9% of evaluators and generally received higher ratings for quality. They were noted for their comprehensive and accurate information, whereas responses from medical professionals were valued for their conciseness. The interrater agreement was fair, indicating some subjectivity but a consistent preference for ChatGPT's detailed responses. Conclusions: ChatGPT demonstrates potential as an effective tool for addressing queries in laboratory medicine, often surpassing medical professionals in response quality. These results support the need for further research to confirm ChatGPT's utility and explore its integration into healthcare settings.

Maternal serum alpha-fetoprotein (AFP) levels are used in screening for open neural tube defects (ONTD). Historical reports show that AFP levels and maternal weights are higher in self-reported Black than White individuals, but recent reports question the need to account for these variables in screening. Our study compares screening performance with and without accounting for race. Retrospective analysis was performed on deidentified prenatal screening records including maternal weight and self-reported race of White or Black. Gestational age-specific medians and weight-adjusted multiples of the median levels were calculated separately for each group and using a race-agnostic analysis. Outcome measures included the proportion of screen-positive results. Records for analysis (n = 13 316) had an ultrasound confirmed gestational age between 15 and 21 completed weeks, singleton pregnancy, and self-reported race. Race was Black for 26.3%. AFP levels for pregnancies in Black individuals were higher than in White individuals: 6% to 11% depending on gestational age. Race-specific gestational age and maternal weight analyses resulted in similar screen-positive rates for self-reported White and Black individuals at 0.74% vs 1.00%, respectively (P = 0.14). However, use of race-agnostic analyses resulted in a screen-positive rate that was 2.4 times higher in Black than White individuals (P < 0.001). These data show that the historical method of accounting for maternal race and weight in prenatal screening for ONTD provides equitable performance. Using a race-agnostic methodology results in an increased screen-positive rate and a disproportionate rate of required follow-up care for individuals who self-identify as Black.

Purpose Respiratory mechanics and the role of sex hormones in pregnancy are not well elucidated. We examined longitudinal and positional changes in lung mechanics in pregnancy and investigated the role of sex hormones. Methods A longitudinal study enrolled 135 women with obesity in early pregnancy. Fifty-nine percent of women identified as White; median body mass index at enrollment was 34.4 kg/m². Women with respiratory disease were excluded. We obtained measurements of airway resistance and respiratory system reactance in various positions using impedance oscillometry and sex hormones in early and late pregnancy. Results With pregnancy progression, there was a significant increase in resonant frequency (Fres) (p = 0.012), integrated area of low frequency reactance (AX) (p = 0.0012) and R5-R20Hz (p = 0.038) in the seated position, and a significant increase in R5Hz (p = 0.000), Fres (p = 0.001), AX (p < 0.001 = 0.000), and R5-R20Hz (p = 0.014) in the supine position. Compared to the seated position, the supine position was associated with a significant increase in R5Hz, R20Hz, X5Hz, Fres, and AX in early (p-values < 0.026) and late pregnancy (p-values ≤ 0.001). Changes in progesterone levels between early and late pregnancy predicted the change in R5, Fres, and AX (p-values ≤ 0.043). Conclusion Resistive and elastic loads increase with pregnancy progression and a change in body position from seated to supine increases resistive and elastic loads in both early and late pregnancies. The increase in airway resistance is primarily related to an increase in peripheral rather than central airways resistance. There was an association between the change in progesterone levels and airway resistance.

Objective: A rolling circle amplification (RCA) based commercial methodology using cell-free (cf)DNA to screen for common trisomies became available in 2018. Relevant publications documented high detection but with a higher than expected 1% false positive rate. Preliminary evidence suggested assay variability was an issue. A multi-center collaboration was created to explore this further and examine whether subsequent manufacturer changes were effective. Methods: Three academic (four devices) and two commercial (two devices) laboratories provided run date, chromosome 21, 18, and 13 run-specific standard deviations, number of samples run, and reagent lot identifications. Temporal trends and between-site/device consistency were explored. Proportions of run standard deviations exceeding pre-specified caps of 0.4%, 0.4% and 0.6% were computed. Results: Overall, 661 RCA runs between April 2019 and July 30, 2022 tested 39,756 samples. In the first 24, subsequent 9, and final 7 months, proportions of capped chromosome 21 runs dropped from 39% to 22% to 6.0%; for chromosome 18, rates were 76%, 36%, and 4.0%. Few chromosome 13 runs were capped using the original 0.60%, but capping at 0.50%, rates were 28%, 16%, and 7.6%. Final rates occurred after reformulated reagents and imaging software modifications were fully implemented across all devices. Revised detection and false positive rates are estimated at 98.4% and 0.3%, respectively. After repeat testing, failure rates may be as low as 0.3%. Conclusion: Current RCA-based screening performance estimates are equivalent to those reported for other methods, but with a lower test failure rate after repeat testing.