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Biomedical subjects

L M Neveux

Publications and source records attributed to L M Neveux.

At least 19 recordsLinked to original sources
PubMed2001

Clinical validation of a new dimeric inhibin-A assay suitable for second trimester Down's syndrome screening.

OBJECTIVE: To compare the Down's syndrome screening performance of a simplified dimeric inhibin-A assay (Diagnostic Systems Laboratories (DSL)) with an assay whose clinical utility has been established (Serotec). SETTING: A case control set consisting of 51 Down's syndrome and 245 matched unaffected pregnancies collected as part of an earlier multicentre cohort study. METHODS: Sera were assayed for dimeric inhibin-A using the DSL assay and Serotec reference assay. Data analysis included a method comparison of mass values, fit of data to a logarithmic Gausian distribution, and determination of detection and false positive rates. In addition, 234 fresh sera were assayed using the simplified method. RESULTS: The two assays showed a high correlation (r = 0.93) but average concentrations of the DSL assay were 48% higher. However, the differences were basically proportional over the range of values important for screening. The detection rate was essentially equivalent for the DSL assay whether analysed univariately or in combination with other markers (for example, 79% v 75% at a 5% false positive rate for the DSL and Serotec assays for the combination of alpha fetoprotein, unconjugated oestriol, human chorionic gonadotrophin, and dimeric inhibin-A, respectively). The 234 dimeric inhibin-A values measured on fresh sera fitted a logarithm Gaussian distribution for the DSL assay, as indicated by the fit to a probability plot. CONCLUSIONS: The Down's syndrome screening performance of a simplified dimeric inhibin-A immunoassay was equivalent to a more labour intensive established dimeric inhibin-A assay.

Adult↗
PubMed2001

Long QT syndrome in children: the value of rate corrected QT interval and DNA analysis as screening tests in the general population.

OBJECTIVE: To evaluate two hypothetical screening strategies for identifying children with long QT syndrome (LQTS), a cause of sudden death in childhood. METHODS: Families with KVLQT1, HERG, or SCN5A genotypes provided electrocardiographic (ECG) data for this analysis. This is the first time such genotype-phenotype information has been available. Using the LQTS genotype, the distributions of QTc in affected and unaffected children were established and screening performance for various QTc cut off points were modelled. The detection rate for DNA mutation analysis was determined from published experience. RESULTS: The mean QTc (SD) was 0.484 seconds (0.031) in 117 affected children and 0.420 seconds (0.021) in 133 unaffected children. A QTc cut off of 0.50 seconds in a population of 1 million children would identify 61 of the 200 affected children, and 100 unaffected children. Estimates of testing costs for a screening programme in the newborn period would be $327 869/case detected and $2 222 000/death avoided. Although not presently available for routine use, DNA analysis could, theoretically, identify 100 of the 200 children with LQTS within the same population, along with an estimated 100 unaffected children. CONCLUSION: The only available screening test for LQTS is ECG measurement. If DNA technology becomes available for screening, unit costs must be very low to be competitive. There are multiple problems with screening for LQTS: only a minority of children will be detected, cost/death avoided is high, and pilot studies would need to be in place for 5-10 years to document efficacy.

Adolescent↗
PubMed2001

Long QT syndrome in children: the value of the rate corrected QT interval in children who present with fainting.

OBJECTIVE: A strategy was evaluated for identifying a proportion of children with long QT syndrome (LQTS) using the rate corrected QT interval (QTc) to systematically evaluate children who faint. METHODS: QTc measurements and rates of fainting for the present analysis are available from families with KVLQT1, HERG, or SCN5A genotypes. QTc distributions in affected and unaffected children were documented and detection and false positive rates were modelled. RESULTS: The mean QTc (SD) in 117 affected children was 0.484 seconds (0.031), and 0.420 seconds (0.021) among 133 unaffected children. At a cut off of 0.49 seconds, QTc measurement will identify 42.5% of affected and 0.1% of unaffected persons with a history of fainting who are alive at the time of testing. Assumptions include a prevalence of 1:5000 for LQTS, 2% mortality with the first arrhythmia, and a rate of fainting of 50% in affected children and 7% in unaffected children. Given these variables, a QTc cut off of 0.49 seconds detects 42 of 200 affected, along with 70 unaffected children out of a population of 1 million. If QTc > or = 0.49 seconds is found in either parent of children with a QTc of 0.44 through 0.48 seconds, another 21 affected and 25 unaffected children will be identified. CONCLUSION: Systematically performing QTc measurements as part of the evaluation of children who faint might optimally identify about one third of patients with LQTS with few false positives and thereby offer an opportunity to prevent some sudden deaths.

Adolescent↗
PubMed2001

Using multiples of the median to normalize serum protein measurements.

Quantification of serum proteins is useful in the diagnosis and clinical management of many disorders. With the introduction of automated analyzers and standardized reference materials, one of the last barriers to more widespread utilization of these measurements is the lack of availability of reliable and transferable age- and gender-specific reference ranges. One normalization method that deserves consideration is converting values to multiples of the median (MoM) for age and gender. When two analytic methods agree, or differ only by a proportional amount, conversion to MoM can be used to simplify the clinical interpretation of serum protein results. As a test of this method, assay results for IgG, transferrin, and albumin from three Swedish hospitals were normalized using published reference ranges from the United States. All assays were standardized to CRM 470. IgG results were in agreement in mass units, and transferrin measurements were proportionally different. However, there were important, non-proportional differences in albumin measurements. After converting IgG and transferrin measurements to MoM, published reference ranges were appropriate for the Swedish Hospitals.

Blood Proteins↗
PubMed2000

Reference distributions for the positive acute phase serum proteins, alpha1-acid glycoprotein (orosomucoid), alpha1-antitrypsin, and haptoglobin: a practical, simple, and clinically relevant approach in a large cohort.

Most clinical conditions are accompanied by corresponding changes in serum levels of some, if not all, of the acute phase proteins. While conditions that affect the acute phase proteins are usually inflammatory in nature, non-inflammatory conditions also can cause changes (e.g., malnutrition, some malignancies without secondary inflammation, and genetic polymorphism). Only after the confounding effects of non-inflammatory conditions are taken into account can these measurements be used to detect and stage the inflammatory process and to evaluate the impact of treatment. In this third article in a series, reference ranges for serum levels for three of the acute phase proteins that increase during inflammation are examined: alpha1-acid glycoprotein (orosomucoid), alpha-antitrypsin, and haptoglobin. The study is based on a cohort of 55,199 Caucasian individuals from northern New England, tested in our laboratory between 1994 and 1999. Measurements were standardized against CRM 470 (RPPHS) and analyzed using a previously described statistical approach. Individuals with unequivocal laboratory evidence of inflammation (C-reactive protein of 10 mg/l or higher) were excluded. Levels of a,-acid glycoprotein changed little during life and between the sexes. Levels of alpha1-antitrypsin varied somewhat by age, rising slightly beyond age 55; males followed a pattern similar to that for females. For this protein, it was necessary to apply two equations to describe the lower levels associated with certain phenotypes. Haptoglobin levels fell significantly during the first decade of life for both males and females and climbed thereafter. Males and females displayed a similar pattern. When values were expressed as multiples of the age- and gender-specific median levels, the resulting distributions fitted a log-Gaussian distribution well over a broad range. When patient data are normalized in this manner, the distribution parameters can be used to assign a centile corresponding to an individual's measurement, thus simplifying interpretation.

Adolescent↗
PubMed2000

Reference distributions for the positive acute phase proteins, alpha1-acid glycoprotein (orosomucoid), alpha1-antitrypsin, and haptoglobin: a comparison of a large cohort to the world's literature.

Limiting bedside use of positive acute phase protein measurements (alpha1-acid glycoprotein (orosomucoid), alpha1-antitrypsin, and haptoglobin) has been the lack of satisfactory methods for quantifying serum levels and a credible reference material. Great strides have been made in the last few years. The remaining barrier to more relevant and cost-effective use of serum protein data for diagnosis and prognosis is the availability of reliable reference intervals from birth to old age for both males and females. Sixty publications reporting reference intervals have been identified which meet the criteria used in our prior two studies, and these have been analyzed statistically. Previous small studies of these individual proteins agree on average, over their constrained age ranges, with our life-long reference ranges. This meta-analysis provides support for our reference ranges and places them in the perspective of previous publications.

Adolescent↗
PubMed1999

Reference distributions for the negative acute-phase serum proteins, albumin, transferrin and transthyretin: a practical, simple and clinically relevant approach in a large cohort.

Inflammation is associated with diverse clinical conditions accompanied by characteristic changes in serum levels of the acute-phase proteins that can be used to stage the inflammatory process and evaluate the impact of treatment. Some acute-phase proteins increase during inflammation, while others, such as albumin, transferrin, and transthyretin, decrease. The current study reports reference ranges for serum levels of albumin, transferrin, and transthyretin based on a cohort of over 124,000 Caucasian individuals from northern New England, tested in our laboratory between 1986 and 1998. Measurements were standardized against CRM 470 (RPPHS) and analyzed using a previously validated statistical approach. Individuals with laboratory evidence of inflammation (C-reactive protein of 10 mg/L or higher) were excluded. The levels of all three analytes varied by age, generally rising until the second or third decade of life and then decreasing thereafter. Albumin and transthyretin levels were higher during midlife among males as compared to females; the maximum being at 25 years for albumin (5%) and 35 years for transthyretin (16%). In contrast, above the age of 10 years, transferrin levels were increasingly higher among females (7% at 20 years). When values were expressed as multiples of the age- and gender-specific median levels, the resulting distributions fitted a log-Gaussian distribution. When patient data are normalized in this manner, the distribution parameters can be used to assign a corresponding centile to an individual's measurement simplifying interpretation. The ultimate interpretation of an individual's measurement relies upon the clinical setting.

Acute-Phase Proteins↗
PubMed1999

Relationship between lipoprotein- and oxidation-related variables and atheroma lipid composition in subjects undergoing coronary artery bypass graft surgery.

The relationship between atheroma lipid composition and serum lipoprotein and oxidation measurements has not been fully explored. To address this question, we studied serum, plasma, and aortic wall specimens from 66 subjects undergoing coronary artery bypass graft surgery. The lipid composition of aortic specimens was characterized in terms of cholesterol ester and cholesterol crystal plus phospholipid by using hot-stage polarizing light microscopy; tissue oxidation status was assessed by measuring conjugated dienes. Serum lipoprotein-related measurements included total cholesterol, triglyceride, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, apolipoproteins B and AI, and lipoprotein(a). Oxidation status was assessed by measuring LDL mobility, thiobarbituric acid-reactive substances, LDL conjugated dienes, and IgG and IgM autoantibodies against oxidized LDL. Fasting blood glucose was also determined. Lesion cholesterol crystal plus phospholipid content was associated inversely with serum HDL cholesterol levels (r=-0.279, P=0.029) and positively with fasting blood glucose (r=0.359, P=0.016), LDL mobility (0.276, P<0.05), and IgM autoantibodies against oxidized LDL (r=0.272, P=0.037). There was also a significant relationship between the level of aortic tissue conjugated dienes and plasma LDL mobility (r=0.332, P=0.007). In multivariate analysis, IgM autoantibodies against oxidized LDL, fasting blood glucose, and LDL mobility, in descending order of significance, together accounted for 35% of the variability in aortic lesion cholesterol crystal plus phospholipid content. These data support direct and independent roles for oxidation and hyperglycemia in the pathophysiology of atherosclerosis.

Aged↗
PubMed1999

Reference distributions for the negative acute-phase proteins, albumin, transferrin, and transthyretin: a comparison of a large cohort to the world's literature.

Clinical interpretation of the acute-phase proteins--albumin, transferrin, and transthyretin--has been hampered by the lack of accurate and precise methods for quantifying the levels and a stable and respected reference material. Now that these issues have been addressed, the community is faced with the need for credible age- and gender-specific reference values. The number of publications that address this issue, even for an analyte as familiar as albumin, is small and, in most cases, such publications lack the relevant data that would allow a combined experience to be created. We have identified 40 studies that meet our criteria: a description of the study participants' health status, of the statistical methodology, and of the laboratory technique and/or reference material used. Few of these studies reported values stratified by gender. A summary of the published median levels by age is presented for the three analytes, along with our own age- and gender-specific medians based on a large cohort. Ten of the studies presented a 95 percent reference range, in close agreement with ours where selection was based upon reported diagnosis rather than upon determination of individual health status. This meta-analysis provides support for the reliability of our recently published methodology and reference data for the clinical interpretation of individual albumin, transferrin, and transthyretin values. As with most laboratory measurements, clinical interpretation requires that other laboratory and clinical factors be considered.

Acute-Phase Proteins↗
PubMed1998

Reference distributions for immunoglobulins A, G, and M: a practical, simple, and clinically relevant approach in a large cohort.

Serum immunoglobulins are measured millions of times each year, yet clinical interpretations remain hampered by inadequate age- and gender-specific reference limits. In order to provide more reliable and comprehensive reference distributions for IgA, IgG, and IgM measurements, we analyzed automated immunoassay values from 115,017 serum samples from northern New England patients (99% Caucasian) who were tested in our laboratory between 1986 and 1995. Measurements were standardized to reference material, CRM 470 (RPPHS). A simple, practical, and clinically relevant approach was used to determine reference distributions for the immunoglobulins over a wide range of ages for males and females. Levels of IgA and IgM varied considerably by age, and by gender for IgM. For each of the analytes, the observed 5th and 95th centiles were symmetric about the median and approximately constant over the entire age range. When immunoglobulin reference values are expressed as multiples of the age- and gender-specific regressed medians, the resulting distributions fit a log-Gaussian distribution well. This finding enables interpretation of serum immunoglobulin measurements using a common unit (multiples of the median) that is independent of age or gender. Insights gained from this study can help improve and simplify the interpretation of immunoglobulin measurements.

Adolescent↗
PubMed1998

The relationship between apolipoprotein E and serum oxidation-related variables is apolipoprotein E phenotype dependent.

To examine the relationship between apolipoprotein E and serum oxidation status, we assayed apolipoprotein E level, apolipoprotein E phenotype, and levels of lipid peroxides and transition metal ions and their binding proteins in sera from apparently healthy individuals. The study group included 129 women aged 22-63 years and 53 men aged 22-56 years. Among subjects with apolipoprotein E 4/3 phenotype, lipid peroxide levels were higher compared with E 3/2 phenotype (786 +/- 182 nmol/l vs. 659 +/- 174 nmol/l, P = 0.015), and ceruloplasmin levels were slightly higher compared with apolipoprotein E 3/3 phenotype (0.28 +/- 0.08 mg/l vs. 0.26 +/- 0.06 mg/l, P = 0.035). In the study group as a whole, there were significant associations between serum apolipoprotein E level, and serum levels of ceruloplasmin (r = 0.266, P < 0.001) and ferritin (r = 0.2, P < 0.007). Among subjects with apolipoprotein E 4/3 phenotype, there was a significant association between serum apolipoprotein E and lipid peroxide levels (r = 0.470, P < 0.01), which was not apparent among subjects with E 3/3 or E 3/2 phenotypes. In multivariate analysis, apolipoprotein E phenotype was a small but significant independent contributor to variation in serum lipid peroxide levels. These data suggest that there may be heterogeneity among apolipoprotein E phenotypes in their relationships with serum lipid oxidation status.

Adult↗
PubMed1998

Second trimester screening for Down's syndrome using maternal serum dimeric inhibin A.

OBJECTIVES: To determine the second trimester Down's syndrome screening performance of maternal serum dimeric inhibin A, both alone and in combination with existing serum markers. SETTING: A case-control set of serum samples from patients with Down's syndrome (52) and subjects with matched unaffected pregnancies obtained in a previous cohort study before second trimester amniocentesis and karyotyping. The amniocenteses were performed for reasons other than a positive serum screening test result. METHODS: For each serum from a Down's syndrome pregnancy, five serum samples from pregnancies with a normal karyotype were matched for recruitment centre, gestational age, maternal age, and date of amniocentesis. A specific form of inhibin (dimeric inhibin A) was measured using monoclonal antibodies. Measurements of alpha fetoprotein, unconjugated oestriol, and human chorionic gonadotrophin and its free beta subunit were already available. Screening performance was modelled using distribution variables of the analytes coupled with the 1993 age distribution of pregnant women in the United States. RESULTS: The median dimeric inhibin A level was 2.10 times higher in Down's syndrome pregnancies. When dimeric inhibin A was combined with maternal age and three other serum markers (alpha fetoprotein, unconjugated oestriol, and human chorionic gonadotrophin) the Down's syndrome detection rate increased to 75% (from 66%) at a 5% false positive rate. If dimeric inhibin A could be added for less than $31 (ranging from $16 to $39 depending on the detection rate, markers chosen, and method of dating), the cost of detecting each Down's syndrome pregnancy and the number of procedure related fetal losses would both be reduced. CONCLUSIONS: The addition of dimeric inhibin A to prenatal screening programmes for Down's syndrome should be considered, or possibly it could be substituted for an existing serum marker. One barrier to implementation in the United States, however, is the unavailability of kits with Food and Drug Administration approval.

Case-Control Studies↗
PubMed1998

hCG and the free beta-subunit as screening tests for Down syndrome.

Published studies have reached varying conclusions as to the benefit of replacing human chorionic gonadotropin (hCG) measurements with the free beta-subunit of hCG (the free beta-subunit) for Down syndrome screening. One study reports 14 per cent higher detection for the free beta-subunit, while another finds an actual loss in detection. To explore this issue further, we directly compared the screening performance of hCG and the free beta-subunit, alone and in combination with other serum markers, using banked sera obtained prior to amniocentesis and karyotyping. Altogether, 52 Down syndrome and 5065 unaffected pregnancies were studied. Sera were thawed and assayed for hCG and the free beta-subunit over 1 year. At a 5 per cent false-positive rate, the detection rate for hCG in combination with maternal age and alpha-fetoprotein was higher than when the free beta-subunit was substituted (62 versus 57 per cent). Ultrasound dating and adding unconjugated oestriol both increased detection. The present findings, along with those from six case control studies (our re-analysis), indicate that the screening performances of hCG and the free beta-subunit are similar (median change in detection 0, range -8 to +3 per cent). Under optimal sample collection and transportation conditions, laboratories can expect to achieve similar screening performance using either hCG or the free beta-subunit measurements.

Amniocentesis↗
PubMed1998

Lipoprotein(a) as a risk factor for ischemic heart disease: metaanalysis of prospective studies.

Although in vitro studies support a pathophysiologic role for lipoprotein(a) [Lp(a)] in the development of atherosclerosis, and retrospective studies consistently report that there is a relationship between Lp(a) and ischemic heart disease (IHD), the conclusions drawn from prospective studies about this relationship have been inconsistent. To address this issue, we have performed a metaanalysis of data available from prospective studies. Lp(a) concentrations expressed as mass units vary markedly between studies, reflecting the need for assay standardization. In 12 of 14 prospective studies, Lp(a) concentrations are higher in subjects who later develop IHD (cases) than in those who do not (controls), although there is variation in the size of the effect. Sample storage temperature may contribute to this variability. When the studies are analyzed collectively, Lp(a) concentrations are significantly higher in cases than in controls, and the extent of the effect is similar in men and women. These findings provide evidence in support of a causal role for Lp(a) in the development of atherosclerosis. Measurement of Lp(a) may be useful to guide management of individuals with a family history of IHD or with existing disease. The separation in values between cases and controls is not, however, sufficient to allow the use of Lp(a) as a screening test in the general population.

Humans↗
PubMed1998

Reference distributions for immunoglobulins A, G, and M: a comparison of a large cohort to the world's literature.

Clinical interpretation of immunoglobulin measurements requires accurate and precise assays and widely accepted reference preparations, as well as reliable age- and gender-specific reference ranges. This last requirement, the topic of numerous publications, has not been addressed adequately. By a combination of computerized and hand searching of the literature from 1961 to 1997, we identified 109 publications presenting IgA, IgG, and/or IgM reference data in healthy individuals. After eliminating studies that lacked appropriate clinical, statistical, or reference material information, data from the 17 acceptable studies were converted to a common reference material, CRM 470/RPPHS. When median levels from our recently published large cohort study are superimposed on these published medians, they fall within the ranges of reported medians. The widths of published 95 percentile reference ranges (where each individual's health was verified) were also found to agree closely with the reference range widths found in our data (where inclusion was based on the reported diagnosis). The current combined study of narrowly applied reference ranges validates our recently published age- and gender-specific reference data for immunoglobulinsA, G, and M. Those new data can now be considered as a source of reliable reference ranges to be used by laboratories when interpreting immunoglobulin measurements.

Cohort Studies↗
PubMed1997

Levels of urinary beta-core fragment, total oestriol, and the ratio of the two in second-trimester screening for Down syndrome.

Levels of beta-core fragment and total oestriol in second-trimester maternal urine samples were measured in 32 Down syndrome pregnancies and 206 control pregnancies. Beta-core fragment and total oestriol values were corrected for the urinary creatinine level and expressed as multiples of the control medians (MOM). In addition, the ratio of the beta-core fragment level to the total oestriol level, without creatinine correction, was calculated, and expressed as MOM values. The median beta-core fragment, total oestriol, and ratio levels in Down syndrome cases were 5.42, 0.64, and 9.32 MOM, respectively. In the Down syndrome pregnancies, 66 per cent of the beta-core fragment levels were above the 95th centile of control levels, while 22 per cent of the total oestriol levels were below the fifth centile of control levels. In combination with maternal age, measurement of beta-core fragment and total oestriol levels in Down syndrome pregnancy resulted in an 80 per cent detection rate at a 5 per cent false-positive rate. Use of the ratio resulted in a univariate detection rate of 72 per cent. In combination with maternal age, the ratio resulted in a detection rate of 81 per cent at a 5 per cent false-positive rate. Based on this unmatched study, the measurement of a ratio of beta-core fragment to total oestriol levels, without the need for creatinine correction, may be useful in screening for fetal Down syndrome in second-trimester urine.

Adult↗
PubMed1996

Multiple marker screening for Down syndrome in twin pregnancies.

This study documents the screening performance, in practice, of a published protocol for interpreting second-trimester Down syndrome risk in twin pregnancies, using maternal serum biochemical markers. Within a cohort of 35,150 pregnancies, 410 twin pregnancies were identified. The rate of twinning was positively associated with maternal age. Of the 274 twin pregnancies known prior to screening, 15 (5.5 per cent) were classified as being screen-positive for Down syndrome. When maternal age and dating method were taken into account, the screen-positive rates in twin and singleton pregnancies did not differ significantly. Nine of the 14 screen-positive women with viable twin pregnancies chose amniocentesis [64 per cent, 95 per cent confidence interval (CI) 35-87]. No cases of Down syndrome were identified. Based on modelling, an estimated 73 per cent of monozygotic twin pregnancies and 43 per cent of dizygotic twin pregnancies with Down syndrome would be identified at a 5 per cent false-positive rate. The overall detection rate would be about 53 per cent. When laboratories offer multiple marker screening to women with twin pregnancies, the false-positive rate ought to be similar to that found in singleton pregnancies; the detection rate is, however, likely to be lower for dizygotic twins.

Adult↗