Biomedical subjects

Louis M Neveux

Publications and source records attributed to Louis M Neveux.

15 recordsLinked to original sources

PubMed2006

Reference distributions for apolipoproteins AI and B and the apolipoprotein B/AI ratios: a practical and clinically relevant approach in a large cohort.

The two serum apolipoproteins in the highest concentrations, apolipoprotein (apo) AI and apolipoprotein B, and the apolipoprotein B/AI ratio are measured to assess clinical risk for atherosclerotic heart and peripheral vascular diseases. The study is based on a cohort of over 37,000 Caucasian individuals from northern New England measured in one laboratory by immunonephelometry using standardized reference materials. All samples received for protein analyses were accepted provided adequate identifying information was available. Laboratory and demographic information was entered into a single database for subsequent study. Our results show that for males without evidence of inflammation, values of apo AI change little through life. For females, however, values gradually increase until about 60 years of age then fall somewhat thereafter. Among adults, females have higher apo AI values on average, than males. Apo B values change significantly through life, increasing after the end of the second decade to a peak during the sixth decade, then falling thereafter. In the past, concern has been expressed that apo AI is an acute phase reactant (APR), thus complicating cardiovascular risk assessment. The effects of an APR (C-reactive protein >or=10 mg/L) on apo AI, but not on apo B, are measurable for both sexes, most noticeably beyond the age of 60 years in males and females. When values were expressed as age- and gender-specific multiples of the median (MoMs), the resulting distributions fit a log-Gaussian distribution well over a broad range. The size of the relatively homogenous cohort, by a standardized approach, provides a firm basis for comparison to preexisting reference intervals and for establishing a clinically useful and current reference interval for the three main apolipoprotein values.

Age Distribution↗

PubMed2006

Reference distributions for apolipoproteins AI and B and B/AI ratios: comparison of a large cohort to the world's literature.

Limiting the clinical utility of apolipoproteins AI (apo AI) and B (apo B) and the apo B/AI ratios until the last decade has been the lack of satisfactory methods for quantifying serum levels and credible reference materials. Great technological 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 has been the availability of widely recognized reliable reference intervals from birth to old age for both males and females. A total of 82 publications reporting reference intervals have been identified that meet most of the same inclusion criteria used in our prior six studies. These have been analyzed statistically and compared to similar studies, i.e., sufficient number, listed subject criteria, method, and reference material, in general terms. Published smaller studies with constrained age ranges, agree on average with our large series of life-long reference intervals that range from less than one year to over 80 years. This study was performed to assess the degree of agreement between smaller reference interval studies to our large population analysis. This meta-analysis provides support and reassurance that many of the smaller reference intervals published previously fall within reasonable limits of out large population.

Age Distribution↗

PubMed2006

Repeated measurement of pregnancy-associated plasma protein-A (PAPP-A) in Down syndrome screening: a validation study.

OBJECTIVES: To confirm that measuring pregnancy-associated plasma protein-A (PAPP-A) in both first- and second-trimester serum samples improves Down syndrome screening. METHODS: We selected paired first- and second-trimester stored serum samples from 34 Down syndrome pregnancies (cases) and 514 unaffected pregnancies (controls) and tested the second-trimester samples for PAPP-A and dimeric inhibin-A (DIA). First-trimester PAPP-A measurements were already available, as were second-trimester measurements of alpha-fetoprotein, unconjugated estriol (uE3), and human chorionic gonadotrophin (hCG). RESULTS: PAPP-A was lower among cases than controls (0.47 MoM) in the first trimester (at an average of 12.5 weeks); in the second trimester, it was not different (0.91 MoM). Using repeated measures of PAPP-A alone, 21 of 34 cases were detected (62%, 95%CI 44% to 78%) with 5% false positives. At an observed 2% false-positive rate, the detection rates (DR) for the quadruple (69%) and serum integrated (69%) tests were lower than for the repeated measures test (75%). Modelled performance at 12 weeks was similar to these observed findings (70, 75, and 82%, respectively). If the first-trimester samples were collected at 10 weeks, however, DR would be higher (70, 81, and 91%, respectively). CONCLUSIONS: Adding a repeated measure of PAPP-A to existing serum markers improves Down syndrome screening to levels that are currently obtainable only by including ultrasound measurement of nuchal translucency (NT). Serum-based screening has the advantages of higher availability and reliability at a lower cost, resulting in a more effective screening strategy. A serum-based repeated measures test has a place in routine Down syndrome screening.

Adult↗

PubMed2006

Comparison of serum markers in first-trimester down syndrome screening.

OBJECTIVE: To estimate patterns of total hCG and inhibin A levels in the late first trimester of Down syndrome pregnancies, compare them with that of free beta-hCG, and assess screening performance of these markers individually and in combination with pregnancy-associated plasma protein-A (PAPP-A) and nuchal translucency. METHODS: Seventy-nine matched case-control sets of maternal serum samples (each Down syndrome case matched to 5 controls) from 11 through 13 completed weeks of gestation were taken from the sample bank of the First and Second Trimester Evaluation of Risk Consortium, a population-based study, and assayed for levels of free beta-hCG, total hCG, and inhibin A. Distribution characteristics and correlations of the multiples of the median values were estimated in cases and controls. Screening performance for each marker, alone and in combination with PAPP-A, nuchal translucency, and maternal age, was calculated. RESULTS: Median multiples of the median levels of free beta-hCG, total hCG, and inhibin A in cases were more elevated as gestation increased from 11 to 13 weeks, with univariate detection rates of 31%, 23%, and 29%, respectively, at a 5% false-positive rate. At 12 weeks, the multivariate detection rates at a 5% false-positive rate for nuchal translucency and PAPP-A (with maternal age) with either free beta-hCG, total hCG, or inhibin A were 84%, 83%, and 85%, respectively. The improvement in performance from nuchal translucency and PAPP-A to any of the three-marker tests was significant, while performance of any of the three-marker combinations was not significantly different from each other. CONCLUSION: Although levels of free beta-hCG in affected pregnancies were higher earlier than the levels of either total hCG or inhibin A, there was no significant difference in screening performance when either of the three markers was used with nuchal translucency and PAPP-A at 11-13 weeks of pregnancy. LEVEL OF EVIDENCE: II-2.

Adult↗

PubMed2005

Maternal serum invasive trophoblast antigen and first-trimester Down syndrome screening.

BACKGROUND: In the United States, Down syndrome screening is still performed mainly in the second trimester, using 3 or 4 markers. Moving screening into the first trimester has the advantage of earlier diagnosis. Currently, first-trimester screening typically includes maternal serum pregnancy-associated plasma protein-A (PAPP-A), the free beta-subunit of human chorionic gonadotropin (free beta), and ultrasound measurement of nuchal translucency thickness (NT). The current report describes a case-control study of serum invasive trophoblast antigen (ITA) and its possible inclusion in first-trimester screening for Down syndrome. METHODS: As part of an earlier observational study, serum samples from 54 Down syndrome and 276 matched unaffected pregnancies were collected between 9 and 15 weeks of gestation. Samples had been aliquoted and stored at -20 degrees C for 8 years. ITA was measured and converted to weight-adjusted multiples of the median (MoM). The distributions of other first-trimester markers are from a single published study. RESULTS: Median ITA MoM in Down syndrome pregnancies increase as gestational age increases (2.02 MoM at 11 and 2.44 MoM at 13 completed weeks). At 75% detection, maternal age in combination with ITA and PAPP-A measurements have an 8.0% false-positive rate, slightly lower than the 8.8% found for the free beta and PAPP-A combination; adding NT measurements reduces false positives for the 2 combinations to 2.0% and 1.8%, respectively. CONCLUSION: Serum ITA appears to be a useful first-trimester Down syndrome marker that could replace free beta measurements while maintaining performance.

Autoanalysis↗

PubMed2005

Integrated serum screening for Down syndrome in primary obstetric practice.

OBJECTIVES: Integrated serum screening for Down syndrome is potentially more effective than current second-trimester screening. We report results of an intervention trial of integrated serum screening that involved 229 primary prenatal care practitioners throughout Maine. METHODS: Women provided a first-trimester serum (for PAPP-A) followed by a second-trimester serum (for AFP, uE3, hCG, and DIA). These five marker measurements were used to calculate a Down syndrome risk in the second trimester. Screen-positive women (risk > or = 1:100) were managed according to standard practice. RESULTS: During 24 months' enrollment, 11 159 women provided a first-trimester sample (61% of women receiving screening services). Nine thousand seven hundred twenty-three women also provided a second-trimester sample; 8773 women satisfied gestational age criteria for testing in both trimesters. Integrated serum screening detected 14 of 16 Down syndrome cases (87%) and 79% after adjustment for trimester-of-ascertainment bias. The initial false-positive rate was 3.2% and was 2.7% when restricted to ultrasound-dated pregnancies. Performance was better than any combination of second-trimester markers. Implementation challenges included initial samples being collected too early and sample matching. CONCLUSIONS: Integrated serum screening for Down syndrome was successfully implemented in primary care settings; screening performance was consistent with predictions. It provides an accessible and acceptable alternative to screening protocols that require nuchal translucency measurements.

Adult↗

PubMed2004

Maternal serum invasive trophoblast antigen (hyperglycosylated hCG) as a screening marker for Down syndrome during the second trimester.

BACKGROUND: Approximately two million pregnancies in the United States are screened for Down syndrome annually by use of second-trimester maternal serum markers. At present, a combination of four markers can identify 75% of affected pregnancies when 5% of screened women are classified as candidates for amniocentesis. Although not currently included in screening panels, invasive trophoblast antigen (ITA) is a promising screening marker in serum or urine in both the second and first trimesters. This study aims at better defining the screening performance of serum ITA in the second trimester. METHODS: In an earlier study, serum samples from an unbiased sampling of 45 Down syndrome (cases) and 238 unaffected (control) pregnancies between 14 and 20 weeks of gestation were collected from various centers in the United States. Samples were aliquoted and stored at -20 degrees C for 8 years. We measured ITA in these samples and determined the screening performance both univariately and in combination with other screening markers. RESULTS: The median ITA in Down syndrome pregnancies was >3.00 multiples of the median, higher than that found for human chorionic gonadotropin (hCG) or free beta-hCG. At a 5% false-positive rate, ITA univariately detected 38% and 40% of Down syndrome pregnancies, respectively, when assigned by date of last menstrual period or ultrasound date. Modeling yielded rates of 45% and 48%. ITA correlated strongly with hCG and free beta-hCG. When substituted for either of these in a multiple marker panel, ITA performed comparably. CONCLUSIONS: This study indicates that serum ITA is an effective marker for Down syndrome. It is highly correlated with both hCG and free beta-hCG and could replace either of them in a multiple marker panel.

Biomarkers↗

PubMed2004

Reference distributions for complement proteins C3 and C4: a comparison of a large cohort to the world's literature.

The lack of credible reference materials and satisfactory methods for quantifying serum levels has limited the bedside use of complement protein (C3 and C4) measurements. However, great technological strides have been made in the last few years. The remaining barrier to a 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. Fifty-one publications reporting reference intervals were identified that meet the criteria used in our prior four studies, and these were analyzed statistically. Previous small studies with constrained age ranges agree, on average, with our larger series of life-long reference ranges. This meta-analysis provides support for our reference ranges and places them in the context of previous publications.

Chemistry, Clinical↗

PubMed2004

Reference distributions for complement proteins C3 and C4: a practical, simple and clinically relevant approach in a large cohort.

The two serum proteins of the complement cascade in the highest concentrations, C3 and C4, respond to various conditions in much the same manner as do other positive acute-phase proteins. A major difference is that they are relatively sluggish in response to cytokine drive, requiring several days rather than hours to be detectably elevated by serial measurements. As with other acute-phase proteins, there are many processes that up- or down-regulate synthesis, including infection or inflammation, hepatic failure, and immune-complex formation. Clinicians may find it difficult to distinguish among these processes, because they often occur simultaneously. The situation is further complicated by genetic polymorphism, with rare instances of markedly reduced synthesis and circulating levels, and consequent vulnerability to infection. C3 and C4 are measured for clinical purposes to help define certain rheumatic and immunologically mediated renal diseases. Interpreting the measured blood levels of these two components requires one to consider the intensity of the inflammatory drive, the timing of the suspected clinical process, the production of complement-consuming immune complexes, and the possible existence of benign circumstances. In this fifth article in a series, reference ranges for serum levels of two complement proteins (C3 and C4) are examined. The study is based on a cohort of over 55,000 Caucasian individuals from northern New England, who were tested in our laboratory in 1994-1999. Measurements were standardized against certified reference material (CRM) 470/reference preparation for proteins in human serum (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. Our results show that the levels of C3 and C4 change little during life and between the sexes, except that they increase slightly and then fall after age 20 in males and at about age 45 in females. 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.

Acute-Phase Proteins↗

PubMed2004

Reference distributions for alpha2-macroglobulin: a practical, simple and clinically relevant approach in a large cohort.

In this 11th article in a series, reference values of serum levels alpha(2)-macroglobulin alpha(2)M) are examined. The study is based on a cohort of 40,420 Caucasian individuals from northern New England that were tested in our laboratory between 1994 and 2000. Measurements were standardized against Certified Reference Material (CRM 470)/Reference Preparation for Proteins in Human Serum (RPPHS) and the results analyzed using a previously described statistical approach. Individuals with unequivocal laboratory evidence of inflammation (C-reactive protein >10 mg/L) were excluded in one leg of the study and included in the other, confirming that alpha(2)M does not respond to acute phase drive in man. Nephrotic syndrome, diabetes mellitus, and chronic liver disease have significant effect on levels of alpha(2)M. Dramatic changes occur during life with males higher from birth to age 12, females thereafter have higher values until the ninth decade. 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↗

PubMed2004

Reference distributions for alpha2-macroglobulin: a comparison of a large cohort to the world's literature.

The lack of satisfactory methods for quantifying serum levels and a credible reference material has limited bedside use of serum alpha(2)-macroglobulin (alpha2M) measurements. 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. A total of 40 publications reporting reference intervals have been identified that meet the criteria used in our prior five studies, and these have been analyzed statistically. On average, previous small studies of these individual proteins agree with our life-long reference ranges over their constrained age ranges. This meta-analysis provides support for our reference ranges and places them in the perspective of previous publications.

Adolescent↗

PubMed2003

Maternal serum-integrated screening for trisomy 18 using both first- and second-trimester markers.

OBJECTIVES: To estimate the prenatal screening performance of an integrated serum test for detecting trisomy 18, which combines measurements of first- and second-trimester markers with maternal age to assign patient-specific risks. METHODS: Published and new observations of maternal serum marker levels in trisomy 18 and unaffected pregnancies are used to derive population parameters. These parameters are then combined in a multivariate Gaussian model to assign patient-specific risks for trisomy 18. RESULTS: The best combination of serum markers includes pregnancy-associated plasma protein-A in the first trimester and alpha-fetoprotein, unconjugated estriol and human chorionic gonadotropin in the second trimester. At a second-trimester risk cutoff of 1 : 100, these 4 markers, in combination with maternal age, detect 90% of trisomy 18 pregnancies at a false-positive rate of 0.1%. The odds of a trisomy 18 pregnancy among screen-positive women are 1 : 4. Without the first-trimester marker, detection is reduced to 67% at about the same false-positive rate. CONCLUSION: The algorithm described here is highly efficient for detecting trisomy 18 and should be considered by programs that offer serum-integrated screening for Down syndrome.

Algorithms↗

PubMed2003

Evaluation of cell-free fetal DNA as a second-trimester maternal serum marker of Down syndrome pregnancy.

BACKGROUND: Second-trimester cell-free fetal DNA (studied only in pregnancies with male fetuses) is higher in maternal serum samples from women carrying Down syndrome fetuses than in unaffected pregnancies. In this study we evaluated the potential performance of fetal DNA as a screening marker for Down syndrome. METHODS: Data on maternal serum fetal DNA concentrations and the corresponding concentrations of the quadruple serum markers were available from 15 Down syndrome cases, each matched for gestational age and length of freezer storage, with 5 control samples. Analyte values were expressed as multiple(s) of the control or population median. Screening performance of fetal DNA, both alone and when added to estimates of quadruple marker performance, was determined after modeling using univariate and multivariate gaussian distribution analysis. RESULTS: The median fetal DNA concentration in Down syndrome cases was 1.7 times higher than in controls. In univariate analysis, fetal DNA gave a 21% detection rate at a 5% false-positive rate. When added to quadruple marker screening, fetal DNA increased the estimated detection rate from 81% to 86% at a 5% false-positive rate. CONCLUSIONS: Cell-free fetal DNA, measured in maternal serum, can modestly increase screening performance above what is currently available in the second trimester. If and when maternal serum fetal DNA can be measured in pregnancies with both male and female fetuses, the utility and cost-effectiveness of adding it as a Down syndrome screening marker should be assessed.

Biomarkers↗

PubMed2002

Reference distributions for serum iron and transferrin saturation: a comparison of a large cohort to the world's literature.

The appropriate clinical use of serum iron and transferrin saturation (TSAT) requires satisfactory reference intervals from birth to old age, and for males and females. This study identified 54 publications from 1974 to 2001 that met the criteria used in three prior meta-analyses, and these were analyzed statistically. A summary of our review is presented along with our reference population data on these measurements. This analysis places previous publications in perspective and suggests possible reasons for the observed differences. Previous studies of the individual analytes, serum iron, transferrin, and TSAT values agree with the reference ranges presented in this study, although the entire experience over time and between sexes has not been available before. Our 95% reference ranges are somewhat broader than those of the smaller studies, but they agree well with those of the larger ones.

Adolescent↗

PubMed2002

Reference distributions for serum iron and transferrin saturation: a practical, simple, and clinically relevant approach in a large cohort.

The principal considerations driving iron status evaluation are clinical concern for anemia and the possibility of iron-storage disease. Most often, the circulating levels of transferrin (or total iron binding capacity) and serum iron are measured and the percentage of transferrin saturation (TSAT) is then computed. Optimally, reference ranges for these analytes should exclude the effects of the acute phase response, nutritional status, estrogen effect, specific genetic disorders, liver disease, and blood transfusion. The current study reports reference ranges for serum iron and TSAT within a cohort of over 55,000 Caucasians from northern New England, tested in our laboratory between 1994 and 1999. Measurements were standardized against serum reference material (SRM) 937 (for iron) and certified reference material (CRM) 470 (also called reference preparation for proteins in human serum (RPPHS)) (for transferrin), and analyzed using a previously published approach. Individual cases with evidence of inflammation (C-reactive protein > or =10 mg/L), or iron overload (TSAT >80% for males and >70% for females) or serum iron values <5 micro mol/L, were removed. Among the referent individuals, iron and TSAT levels rose slightly until the teen years, at which time levels in males increased while those in females remained essentially constant. Between 20 and 70 years of age, males had 10-15% higher iron levels and 15-20% higher TSAT levels than females. When values were expressed as multiples of the age- and gender-specific median levels, the serum iron and TSAT observations fit log-Gaussian distributions reasonably well from the 20th to 99th centile, and the 10th to the 99th centile, respectively. After normalization, the Gaussian parameters can be used to assign a corresponding centile to an individual's measurement, simplifying interpretation. These data provide new and more detailed reference ranges for serum iron and TSAT.

Acute-Phase Proteins↗