348 results on '"Choy KW"'
Search Results
2. Womenʼs preference for non‐invasive prenatal DNA testing versus chromosomal microarray after screening for Down syndrome: a prospective study
- Author
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Cheng, YKY, Leung, WC, Leung, TY, Choy, KW, Chiu, RWK, Lo, T‐K, Kwok, KY, and Sahota, DS
- Published
- 2018
- Full Text
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3. Plasma Angiotensin Converting Enzyme 2 (ACE2) Activity in Healthy Controls and Patients with Cardiovascular Risk Factors and/or Disease
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Lim, HY, Patel, SK, Huang, P, Tacey, M, Choy, KW, Wang, J, Donnan, G, Nandurkar, HH, Ho, P, Burrell, LM, Lim, HY, Patel, SK, Huang, P, Tacey, M, Choy, KW, Wang, J, Donnan, G, Nandurkar, HH, Ho, P, and Burrell, LM
- Abstract
Angiotensin converting enzyme 2 (ACE2) is an endogenous negative regulator of the renin-angiotensin system, a key factor in the development of cardiovascular disease (CVD). ACE2 is also used by SARS-CoV-2 for host cell entry. Given that COVID-19 is associated with hypercoagulability, it is timely to explore the potential relationship between plasma ACE2 activity and the coagulation profile. In this cross-sectional study, ACE2 activity and global coagulation assays (GCA) including thromboelastography, thrombin, and fibrin generation were measured in adult healthy controls (n = 123; mean age 41 ± 17 years; 35% male) and in patients with cardiovascular risk factors and/or disease (n = 258; mean age 65 ± 14 years; 55% male). ACE2 activity was significantly lower in controls compared to patients with cardiovascular risk factors and/or disease (median 0.10 (0.02, 3.33) vs. 5.99 (1.95, 10.37) pmol/mL/min, p < 0.001). Of the healthy controls, 48% had undetectable ACE2 activity. Controls with detectable ACE2 had lower maximum amplitude (p < 0.001). In patients with cardiovascular risk factors and/or disease, those in the 3rd tertile were older and male (p = 0.002), with a higher Framingham grade and increased number of cardiovascular risk factors (p < 0.001). In conclusion, plasma ACE2 activity is undetectable to very low in young healthy controls with minimal clinically relevant associations to GCA. Patients with cardiovascular risk factors and/or disease have increased plasma ACE2 activity, suggesting that it may be an important biomarker of endothelial dysfunction and atherosclerosis.
- Published
- 2022
4. Impaired Fibrinolytic Potential Predicts Oxygen Requirement in COVID-19
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Wang, J, Choy, KW, Lim, HY, Ho, P, Wang, J, Choy, KW, Lim, HY, and Ho, P
- Abstract
Abnormal coagulation and fibrinolysis contributes to the respiratory distress syndrome in COVID-19. We aimed to explore the association of impaired fibrinolytic potential with disease severity and oxygen requirement in hospitalized patients. Adults admitted to hospital with confirmed COVID-19 infection between 1-31 January 2022 were included, corresponding to the first Omicron outbreak in Melbourne, Victoria. The first citrated plasma sample requested within 24 h of the patient's presentation was obtained and analyzed by the overall hemostatic potential (OHP) assay, a spectrophotometric assay in which fibrin formation (triggered by small amounts of thrombin (OCP)) and fibrinolysis (by the addition of thrombin and tissue plasminogen activator (OHP and OFP%)) were simultaneously measured. There were 266 patients (median 72 years, 52.9% male), of which 49.6% did not require oxygen therapy. COVID-19 severity and requirement for oxygen was significantly associated with higher OCP, OHP, and lower OFP%. Vaccinated individuals compared with non-vaccinated individuals had significantly lower OHP (16.5 vs. 23.1, p = 0.015) and higher OFP (72.0% vs. 65.1%, p = 0.005), as well as significantly lower AST, ferritin, LDH, CRP, and D-dimer. A multivariate model containing OHP was constructed with the outcome of oxygen requirement, with c-statistic of 0.85 (95%CI 0.81-0.90). In this pilot study, we show a significant correlation between OHP results and requirement for oxygen supplementation in hospitalized patients during a period dominated by the Omicron variant. The results were incorporated into a multivariate model that predicted for oxygen requirement, with high discriminative ability.
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- 2022
5. Chromosomal abnormalities and neurological outcomes in fetal cerebral ventriculomegaly: a retrospective cohort analysis
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Lok, WY, primary, Kong, CW, additional, Hui, SYA, additional, Shi, MM, additional, Choy, KW, additional, To, WK, additional, and Leung, TY, additional
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- 2021
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6. Intermediate- to long-term outcomes of transvaginal mesh for treatment of Asian women with pelvic organ prolapse
- Author
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Chan, Symphorosa SC, primary, Wan, Osanna YK, additional, Choy, KW, additional, and Cheung, Rachel YK, additional
- Published
- 2021
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7. Contribution of Pathogenic CNVs and Noonan Syndrome in Fetuses with Increased Nuchal Translucency and Persistently Increased Nuchal Fold
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Zeng X, Meng Z, Lin Y, Chau Mhk, Lou J, Liang Y, Dongguan Maternal, Wang H, Zhang W, Yu F, Liu Y, Xie R, Zhang R, Zhong W, Amcare Genomics Lab, Guangzhou, China, Zhu Y, and Choy Kw
- Subjects
Fetus ,medicine.medical_specialty ,business.industry ,Obstetrics ,embryonic structures ,Medicine ,Noonan syndrome ,General Medicine ,business ,medicine.disease ,Increased nuchal translucency ,Nuchal fold - Abstract
Prenatal genetic diagnosis in euploid fetuses with increased Nuchal Translucency (NT) and persistently increased Nuchal Fold (NF) is challenging. The aims of this study is to evaluate the prevalence of pathogenic copy number variants and Noonan Syndrome (NS) in fetuses with increased NT and persistently increased Nuchal Fold (NF) to provide recommendations for pre-natal diagnostic strategies. This is a prospective study from 118 prenatal samples from fetuses with increased NT (≥3.5mm) in first trimester. Multiplex Ligation Dependent Probe Amplification (MLPA), Chromosomal Microarray Analysis (CMA) and karyotyping were conducted. For fetuses with increased NF (≥6mm) in the second trimester with normal karyotype and CMA, targeted Next-Generation Sequencing (NGS) tests for NS were carried out. A total of 118 fetuses had an NT measurement of ≥3.5mm performed MLPA and karyotyping, 89 euploid fetuses were further investigated with CMA, which yielded eight pathogenic CNVs (size ranged from 0.85Mb to 14.5Mb). Twenty fetuses had persistently increased NF at the second trimester. NS testing revealed 3/20 (15%) fetuses had pathogenic variants, and one (5%) with a novel variant of uncertain clinical significance inherited from the father. Our study suggested that NS targeted sequencing facilitates additional genetic diagnosis in fetuses with high NT and persistently increased NF.
- Published
- 2021
8. IUGR is Commonly Observed among Prenatally Diagnosed Chromosome 4p Deletion Syndrome
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Fu Hy, Chan Ym, Huang Hq, Wei Sk, Leung Ty, Su Js, Zhang Sj, Li W, Choy Kw, Yang Sh, Qin Z, Cao Y, Luo Js, Zhu Xf, Lu Wl, Jiang Tt, Zhang Y, and Wei Hw
- Subjects
Genetics ,General Medicine ,Biology ,Chromosome 4p deletion - Abstract
Objective: our study aimed at retrospectively assessing the abnormal prenatal ultrasound findings of chromosome 4p deletion syndrome. Methods: 21 cases with abnormal sonographic signs revealed 4p deletion by Chromosome Microarray (CMA) in this retrospective analysis. Clinical information and molecular basis of this cohort were compared with those from other two groups in China, the critical region related to special ultrasound findings was mapped with the smallest regions of overlap. Results: This is the largest prenatal series to evaluate the prenatal ultrasound features of 4p deletion syndrome detected by CMA. Firstly we refined the relationship between the genomic coordinates with IUGR in chromosome 4p terminal deletion syndrome. Additional chromosomal abnormalities was identified in 12 cases. Intrauterine embryonic arrest was diagnosed at first trimester for 9 cases. The most consistent ultrasound indicator was IUGR (95.5%), and the smallest region response for IUGR correspond to a 2.05Mb at 4p16.3-pter (chr4: 68,345-2,121,057, hg19). Increased Nuchal Translucency (NT) could be a risk factor for predicting WHS at first-trimester pregnancy with the rate of 16.6% from our data. A 3.6Mb microdeletion located at 4p16.3-pter (chr4: 68,345-3,753,422, hg19) might be the candidate region associated with increased NT. Conclusion: We identified IUGR as the most common feature in prenatal 4p terminal deletion and Wolf-Hirschhorn syndrome. The existence of additional CNVs may contribution to possible explanations for the clinical heterogeneity of this syndrome. Prenatal findings of IUGR, increased NT or early spontaneous abortion should warrant the diagnosis of 4p terminal deletion WHS.
- Published
- 2021
9. Global coagulation assays - Proposed reference intervals for healthy controls
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Lim, HY, Choy, KW, Wang, J, Nandurkar, H, Ho, P, Lim, HY, Choy, KW, Wang, J, Nandurkar, H, and Ho, P
- Published
- 2021
10. Expanded carrier screening using next-generation sequencing of 123 Hong Kong Chinese families: a pilot study
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Chan, Olivia YM, primary, Leung, TY, additional, Cao, Y, additional, Shi, MM, additional, Kwan, Angel HW, additional, Chung, Jacqueline PW, additional, Choy, KW, additional, and Chong, SC, additional
- Published
- 2021
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11. Utility of adrenocorticotropic hormone in adrenal vein sampling despite the occurrence of discordant lateralization
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Chee, NYN, Abdul-Wahab, A, Libianto, R, Gwini, SM, Doery, JCG, Choy, KW, Chong, W, Lau, KK, Lam, Q, MacIsaac, RJ, Chiang, C, Shen, J, Young, MJ, Fuller, PJ, Yang, J, Chee, NYN, Abdul-Wahab, A, Libianto, R, Gwini, SM, Doery, JCG, Choy, KW, Chong, W, Lau, KK, Lam, Q, MacIsaac, RJ, Chiang, C, Shen, J, Young, MJ, Fuller, PJ, and Yang, J
- Abstract
BACKGROUND: Adrenal vein sampling (AVS) is crucial for accurate lateralization of aldosterone excess but it is technically challenging due to the difficulty of adrenal vein cannulation. The use of adrenocorticotropic hormone (ACTH) to improve cannulation success is controversial and can lead to discordant lateralization outcomes. OBJECTIVE: To evaluate the utility of ACTH in two centres with different levels of AVS expertise and formulate a strategy for interpreting discordant results. DESIGN: A retrospective cross-sectional analysis of AVS results and postoperative patient outcomes. SETTING: Two large tertiary hospitals with harmonized AVS protocols where adrenal venous samples are collected both before and after ACTH stimulation. MEASUREMENTS: Cannulation success (measured by selectivity index, SI), lateralization (measured by lateralization index, LI) and postoperative biochemical cure. RESULTS: Number of AVS procedures judged to have successful bilateral adrenal vein cannulation increased from 53% pre- to 73% post-ACTH. The increase in cannulation success was significantly higher in centre where AVS was performed by multiple radiologists with a lower basal success rate. In both centres, the proportion of cases deemed to display lateralization significantly decreased with the use of ACTH (70% pre- to 52% post-ACTH). Based on postoperative outcomes of patients with discordant results who underwent unilateral adrenalectomy, the combination of LI >3 pre-ACTH and LI >2 post-ACTH was predictive of a biochemical cure. CONCLUSION: Adrenocorticotropic hormone can increase the rate of cannulation success during AVS at the expense of reduced lateralization. The criteria for lateralization should be carefully determined based on local data when ACTH is used.
- Published
- 2020
12. Adipose-derived stem cells from pregnant women show higher proliferation rate unrelated to estrogen
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Ng, LWC, Yip, SK, Wong, HK, Yam, Gary H., Liu, YM, Lui, WT, Wang, CC, and Choy, KW
- Published
- 2009
13. High isoprostane level in cardinal ligament-derived fibroblasts and urine sample of women with uterine prolapse
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Choy, KW, Liu, YM, Chu, CY, Wang, CC, Lui, WT, Lee, LL, Pang, MW, Rogers, MS, and Yip, SK
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- 2008
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14. MicroRNA from a 12-h versus 20-h acetylcysteine infusion for paracetamol overdose
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Wong, A, primary, Nejad, C, additional, Gantier, M, additional, Choy, KW, additional, Doery, James, additional, and Graudins, A, additional
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- 2019
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15. The short Synacthen test and laboratory assay inter-ference
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Choy, Kw and Choy, Kh
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Male ,Adrenocorticotropic Hormone ,Hydrocortisone ,Clinical Laboratory Techniques ,Posture ,Humans ,Thyrotropin ,Middle Aged ,Dizziness ,False Negative Reactions ,Sensitivity and Specificity ,Blood Chemical Analysis ,Adrenal Insufficiency - Published
- 2017
16. Serum phosphorus levels and fracture following renal transplantation.
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Aleksova, J, Wong, P, Mulley, WR, Choy, KW, McLachlan, R, Ebeling, PR, Kerr, PG, Milat, F, Aleksova, J, Wong, P, Mulley, WR, Choy, KW, McLachlan, R, Ebeling, PR, Kerr, PG, and Milat, F
- Abstract
PURPOSE: Increased fracture rates are observed in renal transplant recipients (RTRs) compared with the general population. Risk factors include age, diabetes, dialysis vintage, immunosuppression and mineral and bone disorders.1 Low serum phosphorus levels occur post-transplantation; however, its relationship with fracture risk has not been evaluated. The purpose of this study was to evaluate risk factors for fracture in RTRs at a single tertiary referral centre. METHODS: A retrospective cross-sectional analysis of 146 patients (75 M, 71 F) who had been referred for dual energy X-ray densitometry (DXA) post-renal transplantation was performed. Aetiology of end stage kidney disease (ESKD), duration of dialysis, parathyroidectomy history, immunosuppression regimen, bone mineral density (BMD), biochemistry and fractures were documented. Statistical analyses included univariable and multivariable regression. RESULTS: The mean age of patients was 54 years and mean time post-transplantation 6.7 years. A total of 79 fractures occurred in 52 patients (35%), with 40 fractures occurring post-transplantation. Ankle/foot fractures were most common (48%). Lower serum phosphorus levels and declining femoral neck (FN) T-score and were associated with fractures in both univariable and multivariable regression analyses after adjusting for age, gender, weight, estimated glomerular filtration rate and pre-transplant history of fracture (P=.011 and P=.042 respectively). The relationship between serum phosphorus and fracture remained significant independent of FN T-score, parathyroid hormone levels, parathyroidectomy status and prednisolone use. CONCLUSION: Fracture was common post-renal transplantation. Lower serum phosphorus levels and declining FN T-scores were associated with fractures. The mechanism of this previously unreported observation requires further evaluation in prospective studies.
- Published
- 2017
17. Debates on fetal fraction measurement and DNA-based noninvasive prenatal screening: time for standardisation?
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Wataganara, T, primary, Bui, T-H, additional, Choy, KW, additional, and Leung, TY, additional
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- 2016
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18. Diagnostic accuracy of the BACs-on-Beads™assay versus karyotyping for prenatal detection of chromosomal abnormalities: a retrospective consecutive case series
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Choy, KW, primary, Kwok, YK, additional, Cheng, YKY, additional, Wong, KM, additional, Wong, HK, additional, Leung, KO, additional, Suen, KW, additional, Adler, K, additional, Wang, CC, additional, Lau, TK, additional, Schermer, MJ, additional, Lao, TT, additional, and Leung, TY, additional
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- 2014
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19. The impact of human copy number variation on a new era of genetic testing
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Choy, KW, primary, Setlur, SR, additional, Lee, C, additional, and Lau, TK, additional
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- 2010
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20. Prenatal diagnosis by array-comparative genomic hybridization
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Chan, LW, primary, Choy, KW, additional, Leung, TY, additional, and Lau, TK, additional
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- 2009
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21. De novo 16p13.11 microdeletion identified by high-resolution array CGH in a fetus with increased nuchal translucency
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Law, LW, primary, Lau, TK, additional, Fung, TY, additional, Leung, TY, additional, Wang, CC, additional, and Choy, KW, additional
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- 2008
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22. Diagnostic accuracy of the BACs-on-Beads™ assay versus karyotyping for prenatal detection of chromosomal abnormalities: a retrospective consecutive case series.
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Choy, Kw, Kwok, Yk, Cheng, Yky, Wong, Km, Wong, Hk, Leung, Ko, Suen, Kw, Adler, K, Wang, Cc, Lau, Tk, Schermer, Mj, Lao, Tt, Leung, Ty, Choy, K W, Kwok, Y K, Cheng, Y K Y, Wong, K M, Wong, H K, Leung, K O, and Suen, K W
- Abstract
Objective: To evaluate the diagnostic performance of the BACs-on-Beads(™) (BoBs(™)) assay for prenatal detection of chromosomal abnormalities.Design: Retrospective study.Setting: Tertiary prenatal diagnosis centre.Population: Women referred for prenatal diagnosis.Methods: We retrieved 2153 archived DNA samples collected between January 2010 and August 2011 for the BoBs(™) assay. These samples had previously been tested by quantitative fluorescence polymerase chain reaction (QF-PCR) and karyotyping. In the BoBs(™) assay a sample was defined as normal disomic when the ratio of the fluorescence intensities in a chromosome locus lay within the threshold (mean ratio ± 2SD), and as deleted or duplicated when the ratio was below the lower threshold (0.6-0.8) or above the upper threshold (1.3-1.4), respectively. The BoBs(™) results were further validated by microarray and compared in a blinded manner with the original QF-PCR and karyotyping results.Main Outcome Measures: Concordance of any numerical, structural, and submicroscopic chromosomal abnormalities between the methods.Results: BACs-on-Beads(™) was similar to karyotyping and QF-PCR in detecting trisomy 13, trisomy 18, trisomy 21, and sex chromosomal aneuploidies, and superior to QF-PCR in detecting major structural abnormalities (53.3 versus 13.3%) and mosaicism (28.6 versus 0%) involving chromosomal abnormalities other than the common aneuploidies. BoBs(™) detected six microdeletion syndromes missed by karyotyping and QF-PCR; however, BoBs(™) missed two cases of triploidy identified by QF-PCR. Therefore, the sensitivity of BoBs(™) is 96.7% (95% CI 92.6-98.7%), and its specificity is 100% (95% CI 99.8-100%).Conclusions: BACs-on-Beads(™) can replace QF-PCR for triaging in prenatal diagnosis, and gives a better diagnostic yield than current rapid aneuploidy tests. [ABSTRACT FROM AUTHOR]- Published
- 2014
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23. Diagnostic accuracy of the BACs-on-Beads™ assay versus karyotyping for prenatal detection of chromosomal abnormalities: a retrospective consecutive case series.
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Choy, KW, Kwok, YK, Cheng, YKY, Wong, KM, Wong, HK, Leung, KO, Suen, KW, Adler, K, Wang, CC, Lau, TK, Schermer, MJ, Lao, TT, and Leung, TY
- Subjects
- *
ELECTRON-transfer catalysis , *DIAGNOSIS methods , *ANEUPLOIDY , *TRISOMY , *NUCLEIC acids - Abstract
Objective To evaluate the diagnostic performance of the BACs-on-Beads™ (BoBs™) assay for prenatal detection of chromosomal abnormalities. Design Retrospective study. Setting Tertiary prenatal diagnosis centre. Population Women referred for prenatal diagnosis. Methods We retrieved 2153 archived DNA samples collected between January 2010 and August 2011 for the BoBs™ assay. These samples had previously been tested by quantitative fluorescence polymerase chain reaction ( QF- PCR) and karyotyping. In the BoBs™ assay a sample was defined as normal disomic when the ratio of the fluorescence intensities in a chromosome locus lay within the threshold (mean ratio ± 2 SD), and as deleted or duplicated when the ratio was below the lower threshold (0.6-0.8) or above the upper threshold (1.3-1.4), respectively. The BoBs™ results were further validated by microarray and compared in a blinded manner with the original QF- PCR and karyotyping results. Main outcome measures Concordance of any numerical, structural, and submicroscopic chromosomal abnormalities between the methods. Results BACs-on-Beads™ was similar to karyotyping and QF- PCR in detecting trisomy 13, trisomy 18, trisomy 21, and sex chromosomal aneuploidies, and superior to QF- PCR in detecting major structural abnormalities (53.3 versus 13.3%) and mosaicism (28.6 versus 0%) involving chromosomal abnormalities other than the common aneuploidies. BoBs™ detected six microdeletion syndromes missed by karyotyping and QF- PCR; however, BoBs™ missed two cases of triploidy identified by QF- PCR. Therefore, the sensitivity of BoBs™ is 96.7% (95% CI 92.6-98.7%), and its specificity is 100% (95% CI 99.8-100%). Conclusions BACs-on-Beads™ can replace QF- PCR for triaging in prenatal diagnosis, and gives a better diagnostic yield than current rapid aneuploidy tests. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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24. The detection of mosaicism by prenatal BoBs[TM].
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Cheng YK, Wong C, Wong HK, Leung KO, Kwok YK, Suen A, Wang CC, Leung TY, and Choy KW
- Abstract
OBJECTIVE: The objective of the study was to evaluate the ability of a new prenatal diagnostic platform - prenatal BACs-on-Beads[TM] (BoBs[TM]) in detecting mosaicism by comparison to quantitative fluorescence-polymerase chain reaction (QF-PCR). METHODS: A validation study of prenatal BoBs[TM] was firstly performed using 18 artificially constructing mosaic samples involving various aneuploidies and microdeletion conditions. Additionally, we compared the accuracy between prenatal BoBs[TM] and QF-PCR for 18 archived clinical mosaic cases and nine chromosomally abnormal cell lines with reference to conventional karyotype results. RESULTS: In the validation study, BoBs[TM] allowed the detection of mosaicism at a level of 20-40%. Among the clinical mosaic cases, 14/18 cases were within the detection of BoBs[TM], 8/14 (57.1%) could be identified by BoBs[TM] and 6/9 (66.7%) by QF-PCR, but 6/14 (42.9%) were missed by both tests. Three cases (16.7%) were detected by prenatal BoBs[TM] but missed by QF-PCR, whereas QF-PCR detected one case that was missed by BoBs[TM]. The overall sensitivity of BoBs[TM] in detecting mosaicism is 44.4% (8/18), which is slightly higher than that of QF-PCR (33.3%; 6/18). CONCLUSION: Prenatal BoBs[TM] has a sensitivity of 57.1% in the detection clinical mosaic cases. According to the validation test, mosaicism of 20% or greater is detectable by the BoBs[TM] assay. © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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25. Prenatal findings and delineation of de novo concurrent partial trisomy 7q(7q31.2 --> qter) and partial monosomy 6q(6q26 --> qter) by high-resolution array CGH.
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Choy KW, Chan LW, Tang MH, Ng LK, Leung TY, and Lau TK
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- 2009
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26. First-trimester cystic hygroma: relationship of nuchal translucency thickness and outcomes.
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Huang J, Leung TY, Choy KW, Huang, Jin, Leung, Tak Yeung, and Choy, Kwong Wai
- Published
- 2013
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27. Contribution of Genomic Imbalance in Prenatal Congenital Anomalies of the Kidney and Urinary Tract: A Multi-Center Cohort Study.
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Li K, Wang H, Chau MHK, Dong Z, Cao Y, Zheng Y, Leung TY, Choy KW, and Zhu Y
- Abstract
Objectives: To investigate the diagnostic utility of copy-number variant (CNV) detection by chromosomal microarray analysis (CMA) and genotype-phenotype associations in prenatal congenital anomalies of the kidney and urinary tract (CAKUT)., Methods: This is a retrospective multi-center study of CNV analysis in 457 fetuses with ultrasound-detected CAKUT and normal karyotypes. Cohorts from published studies were included for further pooled analyses (N = 2746). A literature review of single-nucleotide variant (SNV) and small insertions and deletions (Indel) analysis by whole-exome sequencing was performed to investigate monogenic causes., Results: In our multi-center cohort, 5.3% (24/457) of fetuses had pathogenic CNVs (pCNV); 3.9% (14/359) and 10.2% (10/98) in isolated and non-isolated CAKUT, respectively. Fetuses with isolated hyperechogenic kidneys (HEK) had the highest incidence of having pCNVs. In the literature review, 6.6% (180/2746) of fetuses carried pCNVs; 6.1% and 7.5% in isolated and non-isolated CAKUT, respectively. SNV/Indel analysis provided at least 16.5% (63/381) additional diagnostic yield beyond CNV analysis; 12.8% and 23.8% in isolated and non-isolated CAKUT, respectively., Conclusion: pCNVs comprise a significant proportion of genetic diagnostic findings in prenatal CAKUT, most commonly detected in fetuses with isolated HEK, MCDK, renal agenesis, and non-isolated CAKUT. Monogenic causes should be considered when karyotyping and CMA are nondiagnostic., (© 2024 John Wiley & Sons Ltd.)
- Published
- 2024
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28. Genome sequencing in the prenatal diagnosis of structural malformations in the fetus.
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Chau MHK, Choolani M, Dong Z, Cao Y, and Choy KW
- Abstract
Prenatal genetic diagnosis has undergone two pivotal paradigm shifts, initially with the introduction of chromosomal microarray and subsequently with the advent of next-generation sequencing technologies (NGS). NGS technology has given rise to a multitude of applications, with gene panels, exome sequencing (ES), and genome sequencing (GS) emerging as highly promising tests for prenatal genetic investigations. These advanced approaches have demonstrated superior diagnostic rates when compared to conventional testing methods, showcasing the evolution and enhancement of prenatal genetic screening and diagnostic capabilities. With these ground-breaking innovations, NGS technologies have the potential to replace current standard practice in prenatal diagnosis. With the increasing use of prenatal sequencing, the need for better education and guidance on their applications grows. This chapter aims to illustrate the detection scope and feasibility of various NGS-based methods that are currently used in prenatal diagnosis., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier Ltd.)
- Published
- 2024
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29. Cell-free DNA test for fetal chromosomal abnormalities in multiple pregnancies.
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Kwan AHW, Gil MM, Xue S, Kwok YKY, Lau D, Fung J, Chan A, Choy KW, Leung TY, and Poon LC
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- Humans, Female, Pregnancy, Adult, Chromosome Aberrations, Chromosome Disorders diagnosis, Pregnancy, Twin blood, Retrospective Studies, Prenatal Diagnosis methods, Cell-Free Nucleic Acids blood, Pregnancy, Multiple blood
- Abstract
Introduction: This study aimed to report the screening performance of cell-free DNA (cfDNA) testing for chromosomal abnormalities in twins, triplets, and vanishing twin pregnancies., Material and Methods: Data were obtained from pregnant women with a multiple pregnancy or a vanishing twin pregnancy at ≥10 weeks' gestation who requested self-financed cfDNA testing between May 2015 and December 2021. Those that had positive screening results had diagnostic confirmatory procedures after counseling and consent. The performance of screening of the cfDNA test was determined by calculating confirmation rate and combined false-positive rate (cFPR)., Results: Data from 292 women were included after exclusion of those lost to follow-up, with no-result on cfDNA testing, or had reductions. Of the 292 pregnancies, 10 (3.4%) were triplets, including no cases of trisomy 21 and trisomy 18; 249 (85.3%) were twins, including 3 cases of trisomy 21 and no cases of trisomy 18 and 13; and 33 (11.3%) were vanishing twins, including 3 cases of trisomy 21 and 1 case of trisomy 18. The median (IQR) maternal age was 34 years (31-37). For triplet pregnancies, the initial no-result rate was 10.3% (95% confidence interval [CI] 3.6-26.4), all with results after redraw. For twin pregnancies, the initial no-result rate was 12.9% (95% CI 9.6-17.0), and the no-result rate after redraw was 1.6% (95% CI 0.7-3.6). For vanishing twins, there were no cases with no-result. All triplets had low-risk cfDNA results. The confirmation rate for trisomy 21 was 100% with a FPR at 0% due to the small number of positive cases for twins. For vanishing twins, one high-risk case for trisomy 21 and the only high-risk case for trisomy 18 were confirmed with a cFPR of 8.3% (n = 2/24; 95% CI 2.3-25.9)., Conclusions: cfDNA testing in twin pregnancies has sufficient screening performance for trisomy 21 but the number of affected cases for other conditions is limited to draw any meaningful conclusion. The use of cfDNA testing in triplet pregnancies and vanishing twins remains an area for further research., (© 2024 The Author(s). Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)
- Published
- 2024
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30. Treatment Outcomes of Cesarean Scar Pregnancy Under a Novel Classification System: A Retrospective Cohort Study.
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Yung KK, Lee LLL, Choy KW, Cheung ECW, Chan SSC, and Cheung RYK
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- Humans, Female, Pregnancy, Retrospective Studies, Adult, Treatment Outcome, Methotrexate therapeutic use, Ultrasonography, Prenatal methods, Cohort Studies, Abortifacient Agents, Nonsteroidal therapeutic use, Cicatrix diagnostic imaging, Cesarean Section, Pregnancy, Ectopic diagnostic imaging, Pregnancy, Ectopic surgery, Pregnancy, Ectopic classification
- Abstract
Objectives: To determine whether the new classification system published by Jordans et al for cesarean scar pregnancy (CSP) can guide management and treatment outcomes., Methods: A retrospective study of women diagnosed with CSP from October 2010 to December 2022 in a single tertiary center was performed. Sonographic records of these women were classified into three types according to the classification published by Jordans et al. Treatment outcomes were compared across each type of CSP., Results: The study included a total of 84 women, where 60 (71.4%), 17 (20.2%), and 7 (8.3%) of them were categorized into Type 1, 2, and 3 CSP, respectively. A total of 47 (55.9%) women were managed with methotrexate, 22 (26.2%) underwent surgical management of the CSP without removal of the Cesarean section (CS) niche, and 11 (13.1%) underwent surgery to remove the CSP and the CS niche. Overall treatment success rates for medical management and surgical management were 70 and 97%, respectively. Four women were managed expectantly and continued their pregnancies, among which three carried beyond 34 weeks and had good neonatal outcomes., Conclusions: The classification as published by Jordans et al is easily replicable and readily implemented clinically. Our findings show that a higher proportion of Type 1 and Type 2 CSP were treated successfully by a less invasive medical approach with a high success rate, whereas most Type 3 CSP required surgical resection to successfully remove the CSP and the CS niche. Prospective studies are required to confirm these findings and further validate the clinical utility of this nomenclature system., (© 2024 The Authors. Journal of Ultrasound in Medicine published by Wiley Periodicals LLC on behalf of American Institute of Ultrasound in Medicine.)
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- 2024
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31. Detection of genomic variants by genome sequencing in foetuses with central nervous system abnormalities.
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Wang Y, Liu M, Gao Z, Hua C, Jiang J, Zheng Y, Dong Z, Cao Y, Choy KW, Zhu X, and Kong X
- Subjects
- Humans, Female, Pregnancy, Prospective Studies, Whole Genome Sequencing, Adult, Nervous System Malformations genetics, Nervous System Malformations diagnosis, Nervous System Malformations diagnostic imaging, Fetus abnormalities, Fetus diagnostic imaging, Central Nervous System abnormalities, Central Nervous System diagnostic imaging, Central Nervous System embryology, Male, DNA Copy Number Variations, Prenatal Diagnosis methods
- Abstract
Objective: Clinical validity of genome sequencing (GS) (>30×) has been preliminarily verified in the post-natal setting. This study is to investigate the potential utility of trio-GS as a prenatal test for diagnosis of central nervous system (CNS) anomalies., Methods: We performed trio-based GS on a prospective cohort of 17 foetuses with CNS abnormalities. Single nucleotide variation (SNV), small insertion and deletion (Indel), copy number variation (CNV), structural variant (SV), and regions with absence of heterozygosity (AOH) were analyzed and classified according to ACMG guidelines., Results: Trio-GS identified diagnostic findings in 29.4% (5/17) of foetuses, with pathogenic variants found in SON , L1CAM , KMT2D, and ASPM . Corpus callosum (CC) and cavum septum pellucidum (CSP) abnormalities were the most frequent CNS abnormalities (47.1%, 8/17) with a diagnostic yield of 50%. A total of 29.4% (5/17) foetuses had variants of uncertain significance (VUS). Particularly, maternal uniparental disomy 16 and a de novo mosaic 4p12p11 duplication were simultaneously detected in one foetus with abnormal sulcus development. In addition, parentally inherited chromosomal inversions were identified in two foetuses., Conclusion: GS demonstrates its feasibility in providing genetic diagnosis for foetal CNS abnormalities and shows the potential to expand the application to foetuses with other ultrasound anomalies in prenatal diagnosis.
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- 2024
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32. Copeptin as a surrogate marker for arginine vasopressin: analytical insights, current utility, and emerging applications.
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Choy KW, Wijeratne N, Chiang C, and Don-Wauchope A
- Abstract
Copeptin is a 39-amino-acid long glycosylated peptide with a leucine-rich core segment in the C-terminal part of pre-pro-vasopressin. It exhibits a rapid response comparable to arginine vasopressin (AVP) in response to osmotic, hemodynamic, and nonspecific stress-related stimuli. This similarity can be attributed to equimolar production of copeptin alongside AVP. However, there are markedly different decay kinetics for both peptides, with an estimated initial half-life of copeptin being approximately two times longer than that of AVP. Like AVP, copeptin correlates strongly over a wide osmolality range in healthy individuals, making it a useful alternative to AVP measurement. While copeptin does not appear to be significantly affected by food intake, small amounts of oral fluid intake may result in a significant decrease in copeptin levels. Compared to AVP, copeptin is considerably more stable in vitro . An automated immunofluorescent assay is now available and has been used in recent landmark trials. However, separate validation studies are required before copeptin thresholds from these studies are applied to other assays. The biological variation of copeptin in presumably healthy subjects has been recently reported, which could assist in defining analytical performance specifications for this measurand. An established diagnostic utility of copeptin is in the investigation of polyuria-polydipsia syndrome and copeptin-based testing protocols have been explored in recent years. A single baseline plasma copeptin >21.4 pmol/L differentiates AVP resistance (formerly known as nephrogenic diabetes insipidus) from other causes with 100% sensitivity and specificity, rendering water deprivation testing unnecessary in such cases. In a recent study among adult patients with polyuria-polydipsia syndrome, AVP deficiency (formerly known as central diabetes insipidus) was more accurately diagnosed with hypertonic saline-stimulated copeptin than with arginine-stimulated copeptin. Glucagon-stimulated copeptin has been proposed as a potentially safe and precise test in the investigation of polyuria-polydipsia syndrome. Furthermore, copeptin could reliably identify those with AVP deficiency among patients with severe hypernatremia, though its diagnostic utility is reportedly limited in the differential diagnosis of profound hyponatremia. Copeptin measurement may be a useful tool for early goal-directed management of post-operative AVP deficiency. Additionally, the potential prognostic utility of copeptin has been explored in other diseases. There is an interest in examining the role of the AVP system (with copeptin as a marker) in the pathogenesis of insulin resistance and diabetes mellitus. Copeptin has been found to be independently associated with an increased risk of incident stroke and cardiovascular disease mortality in men with diabetes mellitus. Increased levels of copeptin have been reported to be independently predictive of a decline in estimated glomerular filtration rate and a greater risk of new-onset chronic kidney disease. Furthermore, copeptin is associated with disease severity in patients with autosomal dominant polycystic kidney disease. Copeptin predicts the development of coronary artery disease and cardiovascular mortality in the older population. Moreover, the predictive value of copeptin was found to be comparable with that of N-terminal pro-brain natriuretic peptide for all-cause mortality in patients with heart failure. Whether the measurement of copeptin in these conditions alters clinical management remains to be demonstrated in future studies.
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- 2024
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33. Setting analytical performance specifications for copeptin-based testing.
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Choy KW, Nediyedath K, Farrance I, and Loh TP
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- Humans, Glycopeptides blood, Glycopeptides analysis
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- 2024
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34. Functional study of a rare L1CAM gene c.1759G>C variant prove its pathogenicity.
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Yao Y, Qiu L, Wei X, Chen J, Choy KW, Zheng G, Yang T, Li S, and Yang F
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- Humans, Male, HEK293 Cells, Hydrocephalus genetics, Hydrocephalus metabolism, Hydrocephalus pathology, Pedigree, Infant, Newborn, Mutation, Missense, Neural Cell Adhesion Molecule L1 genetics, Neural Cell Adhesion Molecule L1 metabolism
- Abstract
L1 syndrome, a neurological disorder with an X-linked inheritance pattern, mainly results from mutations occurring in the L1 cell adhesion molecule (L1CAM) gene. The L1CAM molecule, belonging to the immunoglobulin (Ig) superfamily of neurocyte adhesion molecules, plays a pivotal role in facilitating intercellular signal transmission across membranes and is indispensable for proper neuronal development and function. This study identified a rare missense variant (c.1759G>C; p.G587R) in the L1CAM gene within a male fetus presenting with hydrocephalus. Due to a lack of functional analysis, the significance of the L1CAM mutation c.1759G>C (p.G587R) remains unknown. We aimed to perform further verification for its pathogenicity. Blood samples were obtained from the proband and his parents for trio clinical exome sequencing and mutation analysis. Expression level analysis was conducted using western blot techniques. Immunofluorescence was employed to investigate L1CAM subcellular localization, while cell aggregation and cell scratch assays were utilized to assess protein function. The study showed that the mutation (c.1759G>C; p.G587R) affected posttranslational glycosylation modification and induced alterations in the subcellular localization of L1-G587R in the cells. It resulted in the diminished expression of L1CAM on the cell surface and accumulation in the endoplasmic reticulum. The p.G587R altered the function of L1CAM protein and reduced homophilic adhesion capacity of proteins, leading to impaired adhesion and migration of proteins between cells. Our findings provide first biological evidence for the association between the missense mutation (c.1759G>c; p.G587R) in the L1CAM gene and L1 syndrome, confirming the pathogenicity of this missense mutation., (© 2024 John Wiley & Sons Ltd.)
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- 2024
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35. Thalassemia screening by third-generation sequencing: Pilot study in a Thai population.
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Traisrisilp K, Zheng Y, Choy KW, and Chareonkwan P
- Abstract
Background: Conventional thalassemia screening takes a stepwise approach and has limitations in comprehensively identifying all spectrums of mutations. This study aimed to investigate the performance of third-generation sequencing (TGS) compared to conventional molecular testing., Methods: TGS was applied to validate all known variants detected by conventional testing and to detect missing variants in undiagnosed cases. The study was conducted at Maharaj Nakorn Chiang Mai Hospital between December 2021 and April 2022., Results: In total, 19 cases were included in this study, among which 52.6% (10/19) had known thalassemia variants, while 47.7% (9/19) cases were undiagnosed by conventional methods. All 16 variants previously detected were validated by TGS, and TGS additionally detected 43.8% (7/16) thalassemia variants for 36.8% (7/19) cases., Conclusion: TGS could provide additional genetic diagnoses compared with conventional methods. Further cost-effectiveness studies with a larger sample size are needed to explore the role of TGS in clinical practices., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)
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- 2024
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36. Biological Variation Estimates for Plasma Copeptin and Clinical Implications.
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Choy KW, Carobene A, Loh TP, Chiang C, Wijeratne N, Locatelli M, Coskun A, Cavusoglu C, and Unsal I
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- Humans, Male, Female, Adult, Middle Aged, Reference Values, Polyuria blood, Polyuria diagnosis, Polydipsia blood, Polydipsia diagnosis, Young Adult, Glycopeptides blood, Biomarkers blood
- Abstract
Background: Plasma copeptin measurement is useful for the differential diagnoses of polyuria-polydipsia syndrome. It has also been proposed as a prognostic marker for cardiovascular diseases. However, limited information is available about the within- (CVI) and between-subject (CVG) biological variation (BV). This study presents BV estimates for copeptin in healthy individuals., Methods: Samples were collected weekly from 41 healthy subjects over 5 weeks and analyzed using the BRAHMS Copeptin proAVP KRYPTOR assay after at least 8 h of food and fluid abstinence. Outlier detection, variance homogeneity, and trend analysis were performed followed by CV-ANOVA for BV and analytical variation (CVA) estimation with 95% confidence intervals. Reference change values (RCVs), index of individuality (II), and analytical performance specification (APS) were also calculated., Results: The analysis included 178 results from 20 males and 202 values from 21 females. Copeptin concentrations were significantly higher in males than in females (mean 8.5 vs 5.2 pmol/L, P < 0.0001). CVI estimates were 18.0% (95% CI, 15.4%-21.6%) and 19.0% (95% CI, 16.4%-22.6%), for males and females, respectively; RCVs were -35% (decreasing value) and 54% (increasing value). There was marked individuality for copeptin. No result exceeded the diagnostic threshold (>21.4 pmol/L) for arginine vasopressin resistance., Conclusions: The availability of BV data allows for refined APS and associated II, and RCVs applicable as aids in the serial monitoring of patients with specific diseases such as heart failure. The BV estimates are only applicable in subjects who abstained from oral intake due to the rapid and marked effects of fluids on copeptin physiology., (© Association for Diagnostics & Laboratory Medicine 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
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- 2024
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37. A genome-wide association study of Chinese and English language phenotypes in Hong Kong Chinese children.
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Lin YP, Shi Y, Zhang R, Xue X, Rao S, Yin L, Lui KFH, Pan DJ, Maurer U, Choy KW, Paracchini S, McBride C, and So HC
- Abstract
Dyslexia and developmental language disorders are important learning difficulties. However, their genetic basis remains poorly understood, and most genetic studies were performed on Europeans. There is a lack of genome-wide association studies (GWAS) on literacy phenotypes of Chinese as a native language and English as a second language (ESL) in a Chinese population. In this study, we conducted GWAS on 34 reading/language-related phenotypes in Hong Kong Chinese bilingual children (including both twins and singletons; total N = 1046). We performed association tests at the single-variant, gene, and pathway levels. In addition, we tested genetic overlap of these phenotypes with other neuropsychiatric disorders, as well as cognitive performance (CP) and educational attainment (EA) using polygenic risk score (PRS) analysis. Totally 5 independent loci (LD-clumped at r
2 = 0.01; MAF > 0.05) reached genome-wide significance (p < 5e-08; filtered by imputation quality metric Rsq>0.3 and having at least 2 correlated SNPs (r2 > 0.5) with p < 1e-3). The loci were associated with a range of language/literacy traits such as Chinese vocabulary, character and word reading, and rapid digit naming, as well as English lexical decision. Several SNPs from these loci mapped to genes that were reported to be associated with EA and other neuropsychiatric phenotypes, such as MANEA and PLXNC1. In PRS analysis, EA and CP showed the most consistent and significant polygenic overlap with a variety of language traits, especially English literacy skills. To summarize, this study revealed the genetic basis of Chinese and English abilities in a group of Chinese bilingual children. Further studies are warranted to replicate the findings., (© 2024. The Author(s).)- Published
- 2024
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38. Falsely decreased Abbott Alinity-c gamma-glutamyl transferase-2 result from paraprotein and heparin interference: case report and subsequent laboratory experiments.
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Sam KM, Schneider HG, Choy KW, and Lam QT
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- Humans, Male, Female, False Positive Reactions, Heparin, gamma-Glutamyltransferase blood, Paraproteins analysis
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- 2024
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39. Clinical Decision Support in Laboratory Medicine.
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Choy KW, Cornu P, Dighe AS, Georgiou A, Peters L, Sikaris KA, and Loh TP
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- Humans, Decision Support Systems, Clinical
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- 2024
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40. Prenatal Diagnosis and Pregnancy Outcomes of Fetuses With Orofacial Cleft: A Retrospective Cohort Study in Two Centres in Hong Kong.
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Li YY, Tse WT, Kong CW, Wong NKL, Leung TY, Choy KW, To WWK, and Cao Y
- Subjects
- Pregnancy, Female, Humans, Pregnancy Outcome, Hong Kong epidemiology, Retrospective Studies, Ultrasonography, Prenatal, Pregnancy Trimester, First, Prenatal Diagnosis, Fetus diagnostic imaging, Chromosome Aberrations, Microarray Analysis, Cleft Lip diagnostic imaging, Cleft Lip epidemiology, Cleft Lip genetics, Cleft Palate diagnostic imaging, Cleft Palate epidemiology, Cleft Palate genetics
- Abstract
Objective: To evaluate the local incidence of orofacial cleft (OFC) encountered in fetal morphology scan and prenatal diagnosis, genetic etiology of fetuses with or without other structural abnormalities, and their pregnancy outcomes., Design: Retrospective cohort study., Setting: Two maternal fetal medicine units, tertiary hospitals, Hong Kong., Participants: All pregnant women with antenatal diagnosis of fetal OFC between January 2016 and December 2020 (N = 66)., Results: OFC has an incidence of 0.13% among pregnancies in Hong Kong and 28.8% (19/66) were syndromic cleft that exhibited other fetal structural anomalies. There were 55 cases (84.6%) who opted for invasive prenatal diagnostic testing. Genetic defects were identified in 25.8% (17/66) of this cohort, including 14 pathogenic variants. The detection rate in the syndromic cases is 68.4% (13/19) which was significantly higher than 8.5% (4/47) among non-syndromic cases. Aneuploidies would be the most common cause, accounting for 9.1% (6/66). Chromosomal microarray analysis (CMA) provided an incremental diagnostic yield of 6.1% compared to conventional karyotyping. A total of 29 live births including 3 cases of a variant of uncertain significance and 26 cases without genetic abnormalities detected have continued pregnancy to birth. There were 87.5% (21/24) without detectable pathogenic genetic abnormality reported good long-term outcomes. The chance of OFC fetuses having a good long-term outcome was significantly higher if no genomic variant was detected ( P < .001)., Conclusions: Invasive prenatal tests with CMA should be offered to pregnancies with OFC regardless of the type. It has provided incremental diagnostic yield over conventional karyotyping and helped in prenatal and genetic counseling. A negative result in non-syndromic OFC favors couples to keep the pregnancy., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
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- 2024
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41. A review of clinical guidelines, laboratory recommendations and external quality assurance programs for monoclonal gammopathy testing.
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Lim SM, Wijeratne N, Choy KW, Nguyen TTH, Setiawan L, and Loh TP
- Subjects
- Humans, Laboratories, Immunoglobulin Light Chains, Monoclonal Gammopathy of Undetermined Significance diagnosis, Paraproteinemias diagnosis
- Abstract
Monoclonal gammopathy (MG) is a spectrum of diseases ranging from the benign asymptomatic monoclonal gammopathy of undetermined significance to the malignant multiple myeloma. Clinical guidelines and laboratory recommendations have been developed to inform best practices in the diagnosis, monitoring, and management of MG. In this review, the pathophysiology, relevant laboratory testing recommended in clinical practice guidelines and laboratory recommendations related to MG testing and reporting are examined. The clinical guidelines recommend serum protein electrophoresis, serum immunofixation and serum free light chain measurement as initial screening. The laboratory recommendations omit serum immunofixation as it offers limited additional diagnostic value. The laboratory recommendations offer guidance on reporting findings beyond monoclonal protein, which was not required by the clinical guidelines. The clinical guidelines suggested monitoring total IgA concentration by turbidimetry or nephelometry method if the monoclonal protein migrates in the non-gamma region, whereas the laboratory recommendations make allowance for involved IgM and IgG. Additionally, several external quality assurance programs for MG protein electrophoresis and free light chain testing are also appraised. The external quality assurance programs show varied assessment criteria for protein electrophoresis reporting and unit of measurement. There is also significant disparity in reported monoclonal protein concentrations with wide inter-method analytical variation noted for both monoclonal protein quantification and serum free light chain measurement, however this variation appears smaller when the same method was used. Greater harmonization among laboratory recommendations and reporting format may improve clinical interpretation of MG testing.
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- 2024
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42. Prenatal diagnosis of polycystic kidney caused by biallelic hypomorphic variants in the PKD1 gene.
- Author
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Zheng Y, Wong L, Kwan AHW, Dong Z, Kwok KY, Choy KW, Dai H, and Cao Y
- Subjects
- Adult, Female, Pregnancy, Humans, Prenatal Diagnosis, Genetic Association Studies, Exome, Mutation, TRPP Cation Channels genetics, Polycystic Kidney, Autosomal Dominant diagnosis, Polycystic Kidney, Autosomal Dominant genetics
- Abstract
Heterozygous loss-of-function variants in the PKD1 gene are commonly associated with adult-onset autosomal dominant polycystic kidney disease (ADPKD), where the formation of renal cysts depends on the dosage of the PKD1 gene. Biallelic null PKD1 variants are not viable, but biallelic hypomorphic variants could lead to early-onset PKD. We report a non-consanguineous Chinese family with recurrent fetal polycystic kidney and negative findings in the coding region of the PKHD1 gene or chromosomal microarray analysis. Trio exome analysis revealed compound heterozygous variants of uncertain significance in the PKD1 gene in the index pregnancy: a novel paternally inherited c.7863 + 5G > C and a maternally inherited c.9739C > T, p.(Arg3247Cys). Segregation analysis through long-range PCR followed by nested PCR and Sanger sequencing confirmed another affected fetus had both variants, while the other two normal siblings and the parents carried either variant. Thus, these two variants, both of which were hypomorphic as opposed to null variants, co-segregated with prenatal onset polycystic kidney disease in this family. Functional studies are needed to further determine the impact of these two variants. Our findings highlight the biallelic inheritance of hypomorphic PKD1 variants causing prenatal onset polycystic kidney disease, which provides a better understanding of phenotype-genotype correlation and valuable information for reproductive counseling., (© 2023 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)
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- 2024
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43. Renal and extra-renal phenotypes in a fetus with a de novo pathogenic variant in the HNF1B gene.
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Tse WT, Cao Y, Lam PPH, Law KM, Choy KW, and Ting YH
- Subjects
- Adult, Female, Humans, Pregnancy, Fetus diagnostic imaging, Hepatocyte Nuclear Factor 1-beta genetics, Kidney diagnostic imaging, Phenotype, Hernias, Diaphragmatic, Congenital, Kidney Diseases diagnostic imaging, Kidney Diseases genetics
- Abstract
We report a fetus with prenatal ultrasound at 21 gestational weeks showing left cystic renal dysplasia with subcapsular cysts and echogenic parenchyma, right echogenic kidney with absent corticomedullary differentiation, and left congenital diaphragmatic hernia (CDH) with bowel herniation, with intestinal atresia (IA) found on postmortem examination. Whole genome sequencing of fetal blood DNA revealed a heterozygous pathogenic variant c.344 + 2 T>G in the HNF1B gene (NM_000458). Sanger sequencing of the parental samples suggested that it arose de novo in the fetus. HNF1B-associated disorders affect multiple organs with significant phenotypic heterogeneity. In pediatric and adult patients, renal cystic disease and cystic dysplasia are the dominant phenotypes. In prenatal settings, renal anomaly is also the most common presentation, typically with bilateral hyperechogenic kidneys. Our case presented with two uncommon extra-renal phenotypes of CDH and IA besides the typical bilateral cystic renal dysplasia. This association has been reported in fetuses with 17q12 microdeletion but not with HNF1B point mutation. Our case is the first prenatal report of such an association and highlights the possible causal relationship of HNF1B defects with CDH and IA in addition to the typical renal anomalies., (© 2023 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)
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- 2024
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44. Arginine or Hypertonic Saline-Stimulated Copeptin to Diagnose AVP Deficiency.
- Author
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Choy KW
- Subjects
- Humans, Saline Solution, Hypertonic, Arginine, Glycopeptides
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- 2024
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45. Identification of cryptic balanced translocations in couples with unexplained recurrent pregnancy loss based upon embryonic PGT-A results.
- Author
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Li S, Li H, Gao Y, Zou Y, Yin X, Chen ZJ, Choy KW, Dong Z, and Yan J
- Subjects
- Pregnancy, Female, Humans, Translocation, Genetic genetics, Aneuploidy, Blastocyst, Genetic Testing methods, Fertilization in Vitro methods, Preimplantation Diagnosis methods, Abortion, Habitual genetics
- Abstract
Purpose: The goal of this study is to determine whether any balanced translocation (BT) had been missed by previous karyotyping in patients with unexplained recurrent pregnancy loss (uRPL)., Methods: This case series included 48 uRPL-affected couples with normal karyotypes. The embryos from these couples have all undergone preimplantation testing for aneuploidies (PGT-A). Based on the PGT-A's results, 48 couples could be categorized into two groups: 17 couples whose multiple embryos were detected with similar structural variations (SVs, segmental/complete) and 31 couples without such findings but who did not develop any euploid embryo despite at least three high-quality blastocysts being tested. The peripheral blood sample of each partner was then collected for mate-pair sequencing (MPseq) to determine whether any of them were BT carriers., Results: MPseq analyses identified 13 BTs in the 17 couples whose multiple embryos had similar SVs detected (13/17, 76.47%) and three BTs in the 31 couples without euploid embryo obtained (3/31, 9.7%). Among the 16 MPseq-identified BTs, six were missed due to the limited resolution of G-banding karyotyping analysis, and the rest were mostly owing to the similar banding patterns and/or comparable sizes shared by the two segments exchanged., Conclusion: A normal karyotype does not eliminate the possibility of carrying BT for couples with uRPL. The use of PGT-A allows us to perceive the "carrier couples" missed by karyotyping analysis, providing an increased risk of finding cryptic BTs if similar SVs are always detected on two chromosomes among multiple embryos. Nonetheless, certain carriers with translocated segments of sub-resolution may still go unnoticed., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2024
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46. Incremental yield of whole-genome sequencing over chromosomal microarray analysis and exome sequencing for congenital anomalies in prenatal period and infancy: systematic review and meta-analysis.
- Author
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Shreeve N, Sproule C, Choy KW, Dong Z, Gajewska-Knapik K, Kilby MD, and Mone F
- Subjects
- Female, Humans, Infant, Newborn, Pregnancy, Cohort Studies, Exome Sequencing, Microarray Analysis, Ultrasonography, Infant, DNA, Prenatal Diagnosis
- Abstract
Objectives: First, to determine the incremental yield of whole-genome sequencing (WGS) over quantitative fluorescence polymerase chain reaction (QF-PCR)/chromosomal microarray analysis (CMA) with and without exome sequencing (ES) in fetuses, neonates and infants with a congenital anomaly that was or could have been detected on prenatal ultrasound. Second, to evaluate the turnaround time (TAT) and quantity of DNA required for testing using these pathways., Methods: This review was registered prospectively in December 2022. Ovid MEDLINE, EMBASE, MEDLINE (Web of Science), The Cochrane Library and ClinicalTrials.gov databases were searched electronically (January 2010 to December 2022). Inclusion criteria were cohort studies including three or more fetuses, neonates or infants with (i) one or more congenital anomalies; (ii) an anomaly which was or would have been detectable on prenatal ultrasound; and (iii) negative QF-PCR and CMA. In instances in which the CMA result was unavailable, all cases of causative pathogenic copy number variants > 50 kb were excluded, as these would have been detectable on standard prenatal CMA. Pooled incremental yield was determined using a random-effects model and heterogeneity was assessed using Higgins' I
2 test. Subanalyses were performed based on pre- or postnatal cohorts, cases with multisystem anomalies and those meeting the NHS England prenatal ES inclusion criteria., Results: A total of 18 studies incorporating 902 eligible cases were included, of which eight (44.4%) studies focused on prenatal cohorts, incorporating 755 cases, and the remaining studies focused on fetuses undergoing postmortem testing or neonates/infants with congenital structural anomalies, constituting the postnatal cohort. The incremental yield of WGS over QF-PCR/CMA was 26% (95% CI, 18-36%) (I2 = 86%), 16% (95% CI, 9-24%) (I2 = 85%) and 39% (95% CI, 27-51%) (I2 = 53%) for all, prenatal and postnatal cases, respectively. The incremental yield increased in cases in which sequencing was performed in line with the NHS England prenatal ES criteria (32% (95% CI, 22-42%); I2 = 70%) and in those with multisystem anomalies (30% (95% CI, 19-43%); I2 = 65%). The incremental yield of WGS for variants of uncertain significance (VUS) was 18% (95% CI, 7-33%) (I2 = 74%). The incremental yield of WGS over QF-PCR/CMA and ES was 1% (95% CI, 0-4%) (I2 = 47%). The pooled median TAT of WGS was 18 (range, 1-912) days, and the quantity of DNA required was 100 ± 0 ng for WGS and 350 ± 50 ng for QF-PCR/CMA and ES (P = 0.03)., Conclusion: While WGS in cases with congenital anomaly holds great promise, its incremental yield over ES is yet to be demonstrated. However, the laboratory pathway for WGS requires less DNA with a potentially faster TAT compared with sequential QF-PCR/CMA and ES. There was a relatively high rate of VUS using WGS. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology., (© 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.)- Published
- 2024
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47. Screening for and diagnosis of monoclonal gammopathy.
- Author
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Chong YP, Lim SM, Loh TP, Mollee P, Wijeratne N, and Choy KW
- Subjects
- Humans, Monoclonal Gammopathy of Undetermined Significance diagnosis, Multiple Myeloma diagnosis, Multiple Myeloma pathology, Paraproteinemias diagnosis, Precancerous Conditions
- Abstract
Monoclonal gammopathy is a spectrum of disorders characterised by clonal proliferation of plasma cells or lymphocytes, which produce abnormal immunoglobulin or its components (monoclonal proteins). Monoclonal gammopathies are often categorised as low-tumour-burden diseases (eg, amyloid light chain (AL) amyloidosis), premalignant disorders (such as monoclonal gammopathy of undetermined significance and smouldering multiple myeloma), and malignancies (eg, multiple myeloma and Waldenström's macroglobulinaemia). Such diversity of concentration and structure makes monoclonal protein a challenging clonal marker. This article provides an overview on initial laboratory testing of monoclonal gammopathy to guide clinicians and laboratory professionals in the selection and interpretation of appropriate investigations., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2023
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48. Dyslexia-related loci are significantly associated with language and literacy in Chinese-English bilingual Hong Kong Chinese twins.
- Author
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Chung CY, Pan DJ, Paracchini S, Jiang W, So HC, McBride C, Maurer U, Zheng M, and Choy KW
- Subjects
- Adult, Humans, East Asian People, Genome-Wide Association Study, Hong Kong, Language, Membrane Proteins, Nerve Tissue Proteins genetics, Literacy, Dyslexia genetics
- Abstract
A recent genome-wide association study on dyslexia in 51,800 affected European adults and 1,087,070 controls detected 42 genome-wide significant single nucleotide variants (SNPs). The association between rs2624839 in SEMA3F and reading fluency was replicated in a Chinese cohort. This study explores the genetic overlap between Chinese and English word reading, vocabulary knowledge and spelling, and aims at replicating the association in a unique cohort of bilingual (Chinese-English) Hong Kong Chinese twins. Our result showed an almost complete genetic overlap in vocabulary knowledge (r
2 = 0.995), and some genetic overlaps in word reading and spelling (r2 = 0.846, 0.687) across the languages. To investigate the region near rs2624839, we tested proxy SNPs (rs1005678, rs12632110 and rs12494414) at the population level (n = 305-308) and the within-twin level (n = 342-344 [171-172 twin pairs]). All the three SNPs showed significant associations with quantitative Chinese and English vocabulary knowledge (p < 0.05). The strongest association after multiple testing correction was between rs12494414 and English vocabulary knowledge at the within-twin level (p = 0.004). There was a trend of associations with word reading and spelling in English but not in Chinese. Our result suggested that the region near rs2624839 is one of the common genetic factors across English and Chinese vocabulary knowledge and unique factors of English word reading and English spelling in bilingual Chinese twins. A larger sample size is required to validate our findings. Further studies on the relationship between variable expression of SEMA3F, which is important to neurodevelopment, and language and literacy are encouraged., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)- Published
- 2023
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49. A pilot investigation of low-pass genome sequencing identifying site-specific variation in chromosomal mosaicisms by a multiple site sampling approach in first-trimester miscarriages.
- Author
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Li Y, Chau MHK, Zhang YX, Zhao Y, Xue S, Li TC, Cao Y, Dong Z, Choy KW, and Chung JPW
- Subjects
- Pregnancy, Female, Humans, Pregnancy Trimester, First, Mosaicism, Cross-Sectional Studies, Pilot Projects, Abortion, Spontaneous genetics
- Abstract
Study Question: Can multiple-site low-pass genome sequencing (GS) of products of conception (POCs) improve the detection of genetic abnormalities, especially heterogeneously distributed mosaicism and homogeneously distributed mosaicism in first-trimester miscarriage?, Summary Answer: Multiple-site sampling combined with low-pass GS significantly increased genetic diagnostic yield (77.0%, 127/165) of first-trimester miscarriages, with mosaicisms accounting for 17.0% (28/165), especially heterogeneously distributed mosaicisms (75%, 21/28) that are currently underappreciated., What Is Known Already: Aneuploidies are well known to cause first-trimester miscarriage, which are detectable by conventional karyotyping and next-generation sequencing (NGS) on a single-site sampling basis. However, there are limited studies demonstrating the implications of mosaic genetic abnormalities in first-trimester miscarriages, especially when genetic heterogeneity is present in POCs., Study Design, Size, Duration: This is a cross-sectional cohort study carried out at a university-affiliated public hospital. One hundred seventy-four patients diagnosed with first-trimester miscarriage from December 2018 to November 2021 were offered ultrasound-guided manual vacuum aspiration (USG-MVA) treatment. Products of conception were subjected to multiple-site low-pass GS for the detection of chromosomal imbalances., Participants/materials, Setting, Methods: For each POC, multiple sites of villi (three sites on average) were biopsied for low-pass GS. Samples with maternal cell contamination (MCC) and polyploidy were excluded based on the quantitative fluorescence polymerase chain reaction (QF-PCR) results. The spectrum of chromosomal abnormalities, including mosaicism (heterogeneously distributed and homogeneously distributed) and constitutional abnormalities was investigated. Chromosomal microarray analysis and additional DNA fingerprinting were used for validation and MCC exclusion. A cross-platform comparison between conventional karyotyping and our multiple-site approach was also performed., Main Results and the Role of Chance: One hundred sixty-five POCs (corresponding to 490 DNA samples) were subjected to low-pass GS. Genetic abnormalities were detected in 77.0% (127/165) of POCs by our novel approach. Specifically, 17.0% (28/165) of cases had either heterogeneously distributed mosaicism (12.7%, 21/165) or homogeneously distributed mosaicism (6.1%, 10/165) (three cases had both types of mosaicism). The remaining 60.0% (99/165) of cases had constitutional abnormalities. In addition, in the 71 cases with karyotyping performed in parallel, 26.8% (19/71) of the results could be revised by our approach., Limitations, Reasons for Caution: Lack of a normal gestational week-matched cohort might hinder the establishment of a causative link between mosaicisms and first-trimester miscarriage., Wider Implications of the Findings: Low-pass GS with multiple-site sampling increased the detection of chromosomal mosaicisms in first-trimester miscarriage POCs. This innovative multiple-site low-pass GS approach enabled the novel discovery of heterogeneously distributed mosaicism, which was prevalent in first-trimester miscarriage POCs and frequently observed in preimplantation embryos, but is currently unappreciated by conventional single-site cytogenetic investigations., Study Funding/competing Interest(s): This work was supported partly by Research Grant Council Collaborative Research Fund (C4062-21GF to K.W.C), Science and Technology Projects in Guangzhou (202102010005 to K.W.C), Guangdong-Hong Kong Technology Cooperation Funding Scheme (TCFS), Innovation and Technology Fund (GHP/117/19GD to K.W.C), HKOG Direct Grant (2019.050 to J.P.W.C), and Hong Kong Health and Medical Research Fund (05160406 to J.P.W.C). The authors have no competing interests to declare., Trial Registration Number: N/A., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2023
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50. Uncertainty in measurement and the renal tubular reabsorption of phosphate.
- Author
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Farrance I, Frenkel R, and Choy KW
- Subjects
- Humans, Creatinine, Uncertainty, Glomerular Filtration Rate, Phosphates, Kidney Tubules
- Abstract
Objectives: The ratio of tubular maximum reabsorption of phosphate to glomerular filtration rate (TmP/GFR) is used to evaluate renal phosphate transport. TmP/GFR is most probably calculated using the formula described by Kenny and Glen or obtained from the nomogram described by Walton and Bijvoet. Even though the calculation itself is well described, no attention has been given to its measurement uncertainty (MU). The aim of this study is to provide a procedure for evaluating the MU of the Kenny and Glen formula; a procedure which is based on the Evaluation of measurement data - Guide to the expression of uncertainty in measurement (GUM)., Methods: TmP/GFR is a quantity value calculated from the input of measured values for serum (plasma) phosphate and creatinine, plus measured values of urine phosphate and creatinine. Given the measurement uncertainty associated with these input quantities, the GUM describes the mathematical procedures required to determine the uncertainty of the calculated TmP/GFR. From a medical laboratory perspective, these input uncertainties are the standard deviations of the respective internal quality control estimates for serum and urine phosphate, plus serum and urine creatinine., Results: Based on representative measurements for the input quantities and their associated standard uncertainties, the expanded relative uncertainty for a calculated TmP/GFR is approximately 3.0-4.5 %., Conclusions: With the continued relevance of the TmP/GFR procedure and the use of creatinine clearance as an estimate of GFR, the addition of an uncertainty estimate is important as an adjunct to this diagnostic procedure., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)
- Published
- 2023
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- View/download PDF
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