Analysis of the cost effectiveness of different strategies for the antenatal diagnosis of chromosomal aberrations in cases of ultrasound-identified fetal abnormalities.

OBJECTIVE: Principal objective of this work was to analyse the cost effectiveness of different sequences of cytogenetic techniques from the hospital's point of view, after prenatal ultrasound has identified fetal malformations. METHODS: Cytogenetic tests were performed for each case in 3 strategies, and their results are reported and compared to one reference strategy. Two new simulated strategies were considered: chromosomal microarrays alone and a direct test + CMA. MAIN OUTCOMES MEASURES: cost-effectiveness ratio. RESULTS: A single test result was positive in 234 of the 835 pregnancies studied (28%). CMA alone would have identified 239 abnormalities. In the simulated direct test + CMA sequence, the direct test alone would have been positive for 66.1% of the abnormalities identified. When testing was indicated for NT, reference strategy (Direct + karyotyping) costs 1 084.8 euros by positive test results. Strategies Direct + CMA and CMA alone cost respectively 992.7 and 550.0 euros by positive test results. For OUM indications, reference strategy costs 2 937.8 euros by positive test results. Strategies Direct + CMA and CMA alone cost respectively, 2 118.4 and 1 304.7 euros by positive test results. CONCLUSIONS: CMA appears to be the most effective test for prenatal cytogenetic diagnosis of fetal abnormalities identified by ultrasound.

THE PROJECT OF ANOTHER LOW-COST METAPHASE FINDER (SECOND REPORT-APPLICATION OF ARTIFICIAL INTELLIGENCE).

Biological dosimetry is used to estimate individual absorbed radiation dose by quantifying an appropriate biological marker. The most popular gold-standard marker is the appearance of dicentric chromosomes in metaphase. The metaphase finder is a tool for biological dosimetry that finds metaphase cells on glass slides. The author and a software company have designed a new system and are now preparing to produce the system commercially. The metaphase finder consists of an automated microscope, a camera, and a computer. To enhance the accuracy of the system, an artificial intelligence (AI) with deep learning was tested. A total of 1709 images of the metaphase finder detected as 'metaphases' were read into a nine-layer artificial neural network to detect true metaphases. A total of 456 images were used for training, and the rest of the images were used for validation. The accuracy of AI was 0.89 for metaphases and 0.90 for non-metaphases.

Cost-effectiveness of cytogenetic evaluation of products of conception by chorionic villus sampling in recurrent miscarriage.

OBJECTIVE: To compare the cost-effectiveness of performing chorionic villus sampling (CVS) of products of conception (POC) in the evaluation of recurrent miscarriage versus standard evidence-based work-up (EBW) of the couple. MATERIAL AND METHODS: A decision-analytic model was performed in couples with a third miscarriage. Three strategies were considered: (1) the standard EBW of all the patients, comprising parental karyotype, uterine cavity assessment and antiphospholipid antibodies; (2) performing a CVS of POC and a standard karyotype, and if euploid, follow with EBW; and (3) performing a CVS of POC and an arrayCGH and, if normal, follow with EBW. Estimated cost and diagnostic yield of each strategy was analysed. Sensitivity analysis and threshold cost were considered. RESULTS: The expected cost-effectiveness of CVS and karyotype of POC in recurrent miscarriage was: $US769.79 versus $US 1361.8 for the standard EBW of the couple. When stratified by maternal age the results remained cost-effective for this strategy. The arrayCGH strategy has a higher diagnostic yield, but still expensive in our setting to be considered cost-effective. CONCLUSIONS: Chorionic villus sampling and karyotype analysis of products of conception in a third miscarriage proved a more cost-effective strategy than standard EBW of the couple. © 2017 John Wiley & Sons, Ltd.

FISH for 22q11.2 deletion not cost-effective for infants with congenital heart disease with microarray.

The objective of this study is to evaluate the yield of genetic testing in infants with congenital heart disease, who undergo surgical intervention prior to one year of age, and develop a cost-effective strategy to screen infants with congenital heart disease for genetic conditions while providing standard of care. 409 charts of patients with congenital heart disease, who underwent surgical intervention prior to one year of age, were retrospectively reviewed for cytogenetic testing results. 278 patients underwent cytogenetic testing, and 89.6 % of these patients had more than one cytogenetic test completed. The most commonly encountered chromosomal anomaly within the sample was Down Syndrome (12.5 %), followed by 22q11.2 Deletion Syndrome (4.6 %). G-Banded Karyotypes were abnormal in 10.5 % of patients, fluorescence in situ hybridization (FISH) probe for 22q11.2 deletion was abnormal in 7.1 % of patients. SNP microarray testing showed the highest yield and was abnormal in 33 % of patients. Based on the data at our institution, a more directed approach of genetic screening with only microarray would have saved our institution approximately $101, 200 on the 103 patients who underwent genetic evaluation with microarray reviewed. Screening infants with congenital heart disease for 22q11.2 deletion with FISH resulted in a loss of approximately $32,000 per 100 patients at our institution. Institutions should develop microarray-based protocols for genetic screening in patients with congenital heart disease with the anticipation of adding lesion-specific single gene testing as single gene testing becomes routinely available.

An economic analysis of prenatal cytogenetic technologies for sonographically detected fetal anomalies.

When congenital anomalies are diagnosed on prenatal ultrasound, the current standard of care is to perform G-banded karyotyping on cultured amniotic cells. Chromosomal microarray (CMA) can detect smaller genomic deletions and duplications than traditional karyotype analysis. CMA is the first-tier test in the postnatal evaluation of children with multiple congenital anomalies. Recent studies have demonstrated the utility of CMA in the prenatal setting and have advocated for widespread implementation of this technology as the preferred test in prenatal diagnosis. However, CMA remains significantly more expensive than karyotype. In this study, we performed an economic analysis of cytogenetic technologies in the prenatal diagnosis of sonographically detected fetal anomalies comparing four strategies: (i) karyotype alone, (ii) CMA alone, (iii) karyotype and CMA, and (iv) karyotype followed by CMA if the karyotype was normal. In a theoretical cohort of 1,000 patients, CMA alone and karyotype followed by CMA if the karyotype was normal identified a similar number of chromosomal abnormalities. In this model, CMA alone was the most cost-effective strategy, although karyotype alone and CMA following a normal karyotype are both acceptable alternatives. This study supports the clinical utility of CMA in the prenatal diagnosis of sonographically detected fetal anomalies.

Routine application of a novel MLPA-based first-line screening test uncovers clinically relevant copy number aberrations in haematological malignancies undetectable by conventional cytogenetics.

OBJECTIVE: The presence of numerical and/or structural chromosomal abnormalities is a frequent finding in clonal hematopoietic malignant disease, typically diagnosed through routine karyotyping and/or fluorescent in situ hybridization (FISH) analysis. Recently, the application of array comparative genomic hybridization (aCGH) has uncovered many new cryptic genomic copy number imbalances, most of which are now recognized as clinically useful markers of haematological malignancies. In view of the limitations of both FISH and aCGH techniques, in terms of their routine application as a first line screening test, we designed a new multiple ligation-dependent probe amplification (MLPA) probemix for use in addition to classic karyotype analysis. METHODS: A novel MLPA probemix was developed to interrogate copy number changes involving chromosomal regions: 2p23-24 (MYCN, ALK), 5q32-34 (MIR145A, EBF1, MIR146A), 6q21-27, 7p12.2 (IKZF1), 7q21-36, 8q24.21 (MYC), 9p24 (JAK2 V617F point mutation), 9p21.3 (CDKN2A/2B), 9p13.2 (PAX5), 10q23 (PTEN), 11q22.3 (ATM), 12p13.2 (ETV6), 13q14 (RB1, MIR15A, DLEU2, DLEU1), 17p13.1 (TP53), and 21q22.1 (RUNX1/AML1) and was applied to DNA extracted from 313 consecutive bone marrow patient samples, referred for routine karyotype analysis. RESULTS: More than half of the samples originated from newly investigated patients. We discovered clinically relevant genomic aberrations, involving a total of 24 patients (8%) all with a normal karyotype, which would have remained undiagnosed. DISCUSSION: Our data clearly indicate that routine application of this MLPA screening panel, as an adjunct to karyotype analysis, provides a sensitive, robust, rapid and low-cost approach for uncovering clinically important genomic abnormalities, which would have otherwise remained undetected.

Cost-effectiveness of cytogenetic evaluation of products of conception in the patient with a second pregnancy loss.

OBJECTIVE: To compare the cost of two strategies for managing the patient with recurrent pregnancy loss (RPL). DESIGN: Cost analysis using a decision analytic model was used to compare obtaining an evidence-based workup (EBW) for RPL versus obtaining a karyotype of the products of conception (POC) and proceeding with an EBW only in the setting of euploid POC. SETTING: Outpatient care. PATIENT(S): A simulated cohort of patients experiencing a second pregnancy loss. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Total cost of investigating the cause of RPL after a second pregnancy loss. RESULT(S): For all age categories, obtaining a karyotype of POC was less costly than an evidenced-based RPL evaluation. Monte Caro analysis demonstrated a net economic benefit for the karyotype strategy ($4,498 [±$792] vs. $5,022 [±$1,130]). CONCLUSION(S): Our model suggests an economic advantage for obtaining a karyotype of POC in women with second miscarriage.

The utility of end-of-treatment bone marrow aspirates in pediatric acute lymphoblastic leukemia: a quality improvement project.

We reviewed the use, results and costs of end-of-treatment bone marrow aspirates (EOTBMAs) performed locally in patients diagnosed with ALL between 2000 and 2005. Of 193 patients, 188(97%) received EOTBMAs. Though 15/188(8.0%) patients experienced relapse at a median time of 1.1 years (range 0.1-4 years), no sign of relapse was detected on any EOTBMA. After communication of results to clinical staff, only 2/17 (12%) of patients with ALL finishing treatment in the subsequent 5 months received an EOTBMA (P < 0.0001). Our results confirm the futility of EOTBMAs in a large contemporary cohort. Disseminating local results may help ensure adherence to best practices.

Is chromosome testing of the second miscarriage cost saving? A decision analysis of selective versus universal recurrent pregnancy loss evaluation.

OBJECTIVE: To compare the cost of selective recurrent pregnancy loss (RPL) evaluation, which is defined as RPL evaluation if the second miscarriage is euploid, versus universal RPL evaluation, which is defined as RPL evaluation after the second miscarriage. Traditionally, an RPL evaluation is instituted after the third miscarriage. However, recent studies suggest evaluation after the second miscarriage, which dramatically increases health care costs. Alternatively, chromosome testing of the second miscarriage, to determine whether an RPL evaluation is required, has been proposed. DESIGN: Decision-analytic model. SETTING: Academic medical center. PATIENT(S): Couples experiencing a second miscarriage of less than 10 weeks size. INTERVENTION(S): Selective versus universal RPL evaluation after the second miscarriage. MAIN OUTCOME MEASURE(S): Estimated cost for selective versus universal RPL evaluation. RESULT(S): The estimated cost of selective RPL evaluation after the second miscarriage was $3,352, versus $4,507 for universal RPL evaluation, resulting in a cost savings of $1,155. With stratification by maternal age groups, selective RPL evaluation resulted in increased cost savings with advancing maternal age groups. CONCLUSION(S): Selective RPL evaluation, which is based upon chromosome testing of the second miscarriage, is a cost-saving strategy for couples with RPL when compared with universal RPL evaluation. With advancing maternal age groups, the cost savings increased.

Peripheral blood monitoring of chronic myeloid leukemia during treatment with imatinib, second-line agents, and beyond.

BACKGROUND: The current study was conducted to compare simultaneously obtained bone marrow (BM) cytogenetics (CTG), peripheral blood (PB) and BM fluorescence in situ hybridization (FISH), and quantitative real-time polymerase chain reaction (Q-PCR) for BCR-ABL1 in monitoring response to treatment with tyrosine kinase inhibitors and homoharringtonine (HHT) in patients with chronic myeloid leukemia (CML). METHODS: PB and BM FISH (n = 112 samples) and/or Q-PCR (n = 132 samples) for BCR-ABL1 were simultaneously obtained in 70 patients with Philadelphia chromosome-positive (Ph+) CML in chronic (68%), accelerated (16%), and blast phase (16%) before the initiation of therapy and during the course of treatment with imatinib (IM) (n = 40 patients), dasatinib (n = 20 patients), nilotinib (n = 4 patients), bosutinib (n = 18 patients), or HHT (n = 4 patients) for patients with newly diagnosed (n = 13 patients), IM-sensitive (n = 34 patients), IM-resistant (n = 30 patients), or IM-intolerant (n = 9 patients) disease. Eighteen patients were found to have Ph+ variants or karyotypic abnormalities in addition to the Ph+. RESULTS: Excellent correlations (r) were observed between PB and BM FISH (r = 0.95) and PB and BM Q-PCR (r = 0.87), as well as BM CTG and PB FISH (r = 0.89) and PB Q-PCR (r = 0.82). This correlation was not affected by the presence of the Ph+ variant or additional chromosomal abnormalities, the presence of ABL1 kinase domain mutations, phase of the disease, or treatment. CONCLUSIONS: PB FISH and Q-PCR appear to be reliable methods with which to monitor response to modern therapy in patients with all phases of CML.