Access to clinically indicated genetic tests for pediatric patients with Medicaid: Evidence from outpatient genetics clinics in Texas

PurposeLittle is known about how Medicaid coverage policies affect access to genetic tests for pediatric patients. Building upon and extending a previous analysis of prior authorization requests (PARs), we describe expected coverage of genetic tests submitted to Texas Medicaid and the PAR and diagnostic outcomes of those tests.MethodsWe retrospectively reviewed genetic tests ordered at 3 pediatric outpatient genetics clinics in Texas. We compared Current Procedural Terminology (CPT) codes with the Texas Medicaid fee-for-service schedule (FFSS) to determine whether tests were expected to be covered by Medicaid. We assessed completion and diagnostic yield of commonly ordered tests.ResultsAmong the 3388 total tests submitted to Texas Medicaid, 68.9% (n = 2336) used at least 1 CPT code that was not on the FFSS and 80.7% (n = 2735) received a favorable PAR outcome. Of the tests with a CPT code not on the FFSS, 60.0% (n = 1400) received a favorable PAR outcome and were completed and 20.5% (n = 287) were diagnostic. The diagnostic yield of all tests with a favorable PAR outcome that were completed was 18.7% (n = 380/2029).ConclusionMost PARs submitted to Texas Medicaid used a CPT code for which reimbursement from Texas Medicaid was not guaranteed. The frequency with which clinically indicated genetic tests were not listed on the Texas Medicaid FFSS suggests misalignment between genetic testing needs and coverage policies. Our findings can inform updates to Medicaid policies to reduce coverage uncertainty and expand access to genetic tests with high diagnostic utility.     

Rapid diagnosis of early ectopic pregnancy in an emergency gynaecology service--are measurements of progesterone, intact and free {beta} human chorionic gonadotrophin helpful?

The clinical usefulness of measuring serum concentrations ofprogesterone, human chorionic gonadotrophin (HCG) and the free-subunit of HCG in distinguishing between early viable and non-viablepregnancy, before an accurate ultrasound diagnosis is possible,was evaluated in a prospective study of patients presentingto our emergency gynaecology service with a clinical suspicionof ectopic pregnancy. Patients were selected on the basis ofinitial HCG concentrations; samples with HCG 25–10 000IU/I were later analysed for progesterone and free HCG. Of the181 patients studied, 38 (21%) had an ectopic pregnancy, 108(60%) had a spontaneous abortion and 35 (19%) had a viable intra-uterinepregnancy. Concentrations of HCG and free HCG in the group withviable pregnancies were significantly higher than in the groupwith ectopic pregnancy (P < 0.001) and than those destinedto miscarry (P < 0.01). Progesterone concentrations werealso significantly higher in the viable versus the ectopic andthe spontaneous abortion groups (P < 0.001 in each case).Despite these highly significant differences there was a degreeof overlap such that it was impossible to devise a cut-off levelfor any hormone analysed, either singly or in combination, whichwould offer a clinically useful predictor of outcome.     

Locating human quantitative trait loci: Guidelines for the selection of sibling pairs for genotyping

Simulation studies were conducted to assess the relative merits of different nonrandom sampling strategies for the selection of sibling pairs for genotyping in the attempt to locate individual loci (QTLs) contributing to variation in human quantitative traits. For a constant amount of variation contributed by a QTL (25% of the total) the frequencies and dominance relationships of a trait increasing allele were varied. Three strategies for selection of pairs for genotyping were based on the phenotypic values of the siblings: Concordant sib pairs (CSP) are pairs in which both individuals exceed a given threshold value; discordant sib pairs (DSP) are pairs in which one member exceeds a given upper threshold and the other is below a specified lower threshold; and most similar pairs (MSP) are pairs selected for falling below a specified percentile ranking of the within-pair mean square for the quantitative trait. Tests for linkage with markers at 1, 2, 5, 10, and 20 cM from each of the QTLs were conducted for each of the selected samples and compared with tests based on the regression, in the entire sample, of within pair variation on the proportion of alleles identical by descent (IBD) at each marker locus. Tests for the effect of the increasing allele at the QTL (candidate gene) were also conducted for the DSP pairs. No single nonrandom selection procedure yields as much as half the information realized in the total sample. However, a combined strategy which involves genotyping the 5% of MSP and DSP for the upper and lower quintiles of values of the quantitative trait (a further 3% of the sample approximately) yields lod scores which are usually more than 65% of the values realized for the entire sample. Tests comparing the proportion of increasing alleles in high- and low-scoring siblings from DSP samples are uniformly very powerful for detecting candidate loci. Even when it is not possible to measure the entire range of the phenotype with uniform precision, some attempt to differentiate among individuals in a common unaffected class of individuals can lead to considerable increase in power.     

DADE DIMENSION—RXL型全自动生化分析仪性能评价

目的：评价美国杜邦ＤＩＭＥＮＳＩＯＮ—ＲＸＬ全自动生化分析仪的工作性能。方法：用ＤＡＤＥ试剂及定值血清对该仪器的准确度、精密度及交叉污染等进行了观察。结果：对包括酶活性及电解质在内的十二项待测物进行了测试,其结果均位于可信范围内。精密度观察：批内不精密度的ＣＶ％为０．０７－１．４５％,批间不精密度ＣＶ％为０．５８－１．９５％。交叉污染率为０－０．５５１％。结论：通过准确度、精密度和交叉污染实验观察,作者认为该仪器可以满足临床化学实验室的要求。     

卟啉生物化学研究概况

本文在卟啉的化学结构和分类、化学检测方法、化学合成以及卟啉生物合成等方面对卟啉生物化学的研究概况进行综述。     

重组人神经营养因子-4/5蛋白抗三氧化二砷神经毒作用

目的初步观察重组人神经营养因子-4／5（hNT－4／5）蛋白对三氧化二砷毒性的抑制作用。方法利用hNT－4／5蛋白具有抗神经毒性的特点,采用本实验室克隆表达及部分纯化的具有天然hNT－4／5蛋白生物学活性的重组hNT-4／5蛋白,以不同水平的重组hNT4／5蛋白（0－100μl）与不同浓度的As2O3（0－160μmol／L）同时加入各组鸡胚前脑神经细胞和PC12细胞培养液中共同孵育24－48小时,观察其对染毒鸡胚前脑神经细胞存活和PC12细胞突起生长的影响作用。结果在鸡胚前脑神经细胞和PC12细胞中与As2O3共同培养48小时后,对照组与实验组的细胞存活率差异有显著性,而且细胞存活率和突起数目随hNT－4／5浓度增高而提高和增加。结论初步观察到重组hNT4／5蛋白具有抑制As2O3的毒性作用,为从基因工程途径寻找抗环境毒物因子提供了依据。     

MDA in plasma as a biomarker of exposure to pyrolysed MDI-based polyurethane: correlations with estimated cumulative dose and genotype for N-acetylation

The object of this study was to investigate whether exposure of pipe-layers to thermal degradation products of diphenylmethane diisocyanate (MDI) could be assessed by analysing 4,4-methylenedianiline (MDA) in hydrolysed plasma and urine, and whether the genotype for N-acetylation affected these biomarker levels. Blood and urine samples were drawn from 30-pipe-layers who had been welding polyurethane (PUR) insulated pipes during the preceding 3 months. MDA in hydrolysed plasma and urine was determined with a gas chromatography-mass spectrometry technique, and genotype for N-acetylation was analysed with a polymerase chain reaction technique. MDA in plasma was detected in 18 of the 30 pipe-layers. Their plasma concentrations of MDA varied from 0.05 to 8.48 g/1. There was a significant negative correlation between time since last welding of PUR-insulated pipes and P-MDA (r _s = 0.50, P = 0.005). There was also a significant positive correlation between the estimated number of welded PUR-insulated pipes during the preceding 3 months and P-MDA (r _s = 0.68, P = < 0.001). No significant association between genotype of N-acetylation and P-MDA was observed in a multiple regression analysis when adjustment was made for the estimated cumulative exposure to thermal degradation products of MDI. MDA in urine was detected in only four of the 30 pipe-layers. These four subjects had been welding PUR pipes on the same day as the sampling, or on the day before. The present results indicate the spot plasma samples analysed for MDA may give a rather good estimate of exposure to MDI during the preceding months. P-MDA, but not U-MDA, therefore seems to be a useful biomarker of long-term exposure to MDI. The individual N-acetylation capacity did not affect the plasma levels of MDA.     

5-Methyltetrahydrofolate for biochemical modulation of fluorouracil (FU) in patients with advanced colorectal cancer: A randomized phase I--II study of two different FU administration schedules

Background: To determine the maximum tolerable dose (MTD) and therapeutic activity of MTHF-modulated FU using two different administration schedules of the antimetabolite (bolus vs. two-hour infusion), the present randomized study using a 'pick-the-winner' design was undertaken in patients with advanced colorectal cancer.Patients and methods: Eighty-two patients with previously untreated advanced measurable colorectal cancer were randomly assigned to treatment with MTHF (100 mg/m2 days 1–5 i.v. bolus) plus FU (400 mg/m2 days 1–5) given either as i.v. bolus injection or as a two-hour infusion every four weeks. In the absence of dose-limiting toxicity (DLT, defined as WHO grade 3 hematotoxicity and/or WHO grade 2 nonhematologic side effects) and evidence of progressive disease, the FU dose was escalated by 50 mg/m2/day during each subsequent cycle until the individual maximum tolerable dose (MTD) was reached.Results: Forty patients were randomized to the FU bolus arm and 42 patients to the FU two-hour infusion arm. The median MTD was 475 mg/m2/day (95% CI: 450–500) in the FU bolus arm with stomatitis ± diarrhea being the most common DLT. Gastrointestinal side effects were also dose-limiting in the two-hour infusion arm; however, the median MTD was 600 mg/m2/day (95% CI: 568–632). Myelosuppression was more pronounced in the FU bolus arm than in the two-hour infusion arm. The overall response rates were 27.5% (95% CI: 15–44%; 1 CR and 10 PR) for patients treated in the bolus arm and 14.5% (95% CI: 5–28%; 1 CR and 5 PR) for those treated in the two-hour infusion arm. Analogous to recorded response, median time to progression (8.5 vs. 6.25) and overall survival time (14.0 vs. 11.0) tended to be superior in the FU bolus arm.Conclusions: The observed differences in tolerable drug dose and toxicity between the two treatment arms might be explained by the administration schedule-dependent clinical pharmacokinetics of FU and/or the difference in extent of biochemical modulation of the antimetabolite through MTHF. The fact that the two regimens were not equitoxic probably also helps to explain the favourable response activity noted in the MTHF/FU bolus arm. Whether MTHF is as effective as leucovorin for biochemical modulation of FU remains to be determined in a randomized trial, for which we would recommend its combined use with bolus FU ('winner arm') using a starting dose of 400 mg/m2/day ×5.     

Diffusion of information about genetic risk within families

Recent developments in genetics are likely to exacerbate the ethical issues in clinical practice, especially with regard to privacy and disclosure of genetic information. To evaluate the behaviour of patients with respect to transmitting carrier information, we undertook a survey of 283 families with a balanced chromosomal rearrangement as a model. In these families, 1816 relatives were considered at risk and 806 of them were karyotyped (44.4%). The percentage of karyotypes performed is significantly related to the number of living children of the index couple, the reason for referral, the nature of the anomaly, the training of the counsellor and the age of the index case. This study shows the limits of the screening of at risk individuals within families, based on the willingness of the patients, and addresses practical and ethical issues around family disclosure in medical genetics.