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Biomedical subjects

G J Knight

Publications and source records attributed to G J Knight.

At least 19 recordsLinked to original sources
PubMed2004

The reference range and within-person variability of thyroid stimulating hormone during the first and second trimesters of pregnancy.

OBJECTIVE: To further explore first and second trimester reference ranges for thyroid stimulating hormone (TSH) and examine within-person variability of TSH and thyroid peroxidase (TPO) antibody. SETTING: Women coming for routine prenatal care in early pregnancy agreed to participate in a trial of integrated serum screening for Down's syndrome. Two serum samples were obtained from each woman, one each in the first and second trimesters. These samples were also available for TSH and TPO measurements in the present study. METHODS: TSH and TPO antibody measurements were performed in 1126 women with ultrasound-dated pregnancies who provided serum samples in both trimesters. TSH reference ranges were established for the entire cohort and for the antibody-negative subgroup. Within-person variability of TSH measurements between trimesters was examined. RESULTS: Median TSH values are lower in the first trimester than in the second (1.00 versus 1.29 mIU/l), but 98th centile values are higher (5.20 versus 4.18 mIU/l). High correlation exists between individual women's first and second trimester TSH measurements (r=0.75, r2=0.56, p<0.001). Among 23 women with TSH values above the 98th centile in the second trimester, 17 (74%) were over the 95th centile in the first trimester. TPO antibody measurements are also highly correlated between trimesters (r=0.97, r)=0.94). CONCLUSION: Proper interpretation of TSH measurements during pregnancy requires that laboratories establish and monitor appropriate reference ranges. TSH levels show high within-person consistency between trimesters.

Female↗
PubMed2002

Assigning risk for Smith-Lemli-Opitz syndrome as part of 2nd trimester screening for Down's syndrome.

OBJECTIVES: To design a reliable model in the context of prenatal screening for assigning the risk in an individual pregnancy of Smith-Lemli-Opitz syndrome (SLOS) and assess its performance. SETTING: A 2nd trimester screening programme for Down's syndrome that measures unconjugated estriol (uE3) along with other serum markers. METHODS: Development of individual risk estimates with a trivariate model incorporating measurements of maternal serum uE3, alpha-fetoprotein (AFP), and human chorionic gonadotropin (hCG) in both SLOS and unaffected pregnancies. RESULTS: Population parameters were computed for the three analytes, as were pairwise correlation coefficients and truncation limits, based on an unbiased collection of 29 affected pregnancies. Published parameters were used for unaffected pregnancies. With a cut off level of risk of 1:50, 62% of SLOS pregnancies can be detected by initially identifying 0.34% of unaffected pregnancies as screen positive. About 1 in 90 screen positive pregnancies will be affected. CONCLUSIONS: It is possible to screen for SLOS as an add on to existing 2nd trimester maternal serum screening, if uE3 is already being measured. A large, prospective trial is necessary to determine whether diagnostic testing can be performed in maternal urine or serum rather than amniotic fluid.

Biomarkers↗
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↗
PubMed1999

Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child.

BACKGROUND: When thyroid deficiency occurs simultaneously in a pregnant woman and her fetus, the child's neuropsychological development is adversely affected. Whether developmental problems occur when only the mother has hypothyroidism during pregnancy is not known. METHODS: In 1996 and 1997, we measured thyrotropin in stored serum samples collected from 25,216 pregnant women between January 1987 and March 1990. We then located 47 women with serum thyrotropin concentrations at or above the 99.7th percentile of the values for all the pregnant women, 15 women with values between the 98th and 99.6th percentiles, inclusive, in combination with low thyroxine levels, and 124 matched women with normal values. Their seven-to-nine-year-old children, none of whom had hypothyroidism as newborns, underwent 15 tests relating to intelligence, attention, language, reading ability, school performance, and visual-motor performance. RESULTS: The children of the 62 women with high serum thyrotropin concentrations performed slightly less well on all 15 tests. Their full-scale IQ scores on the Wechsler Intelligence Scale for Children, third edition, averaged 4 points lower than those of the children of the 124 matched control women (P= 0.06); 15 percent had scores of 85 or less, as compared with 5 percent of the matched control children. Of the 62 women with thyroid deficiency, 48 were not treated for the condition during the pregnancy under study. The full-scale IQ scores of their children averaged 7 points lower than those of the 124 matched control children (P=0.005); 19 percent had scores of 85 or less. Eleven years after the pregnancy under study, 64 percent of the untreated women and 4 percent of the matched control women had confirmed hypothyroidism. CONCLUSIONS: Undiagnosed hypothyroidism in pregnant women may adversely affect their fetuses; therefore, screening for thyroid deficiency during pregnancy may be warranted.

Adult↗
PubMed1999

Invasive meningococcal infection in Western Australia.

OBJECTIVES: To review signs and symptoms in children diagnosed with meningococcal infection; to assess age, sex and race distribution of meningococcal infection; and to assess associations of the presenting features with morbidity and mortality. DESIGN: Retrospective case notes review for a 5-year period. SUBJECTS: 105 patients aged between 19 days and 13 years. MAIN DATA REVIEWED: Temperature, blood pressure, heart rate, respiratory rate, type of rash, age, sex, race and outcome. RESULTS: Of the 105 patients, 67.6% were Caucasian, 27.6% Aboriginal and 4.8% of other origin. There were 14.3% patients under 3 months of age (2.9% neonates), 48.6% between 3 months and 2 years, 21% between 2 and 4 years and 16.2% older than 4 years. The male:female ratio was 1.4. Features at presentation in decreasing order of frequency were: fever (89.5%), tachypnoea (73.3%), rash (59% [maculopapular 17.1%, petechial 27.6% and purpuric 14.3%]), vomiting (52.4%), irritability (44.8%), tachycardia (37.5%), lethargy (36.2%), neck stiffness (32.4%) and non-specific immediately preceding illness (15.2%). Purpura and a reduced systolic blood pressure were significantly associated with an increased risk of mortality, purpura and reduced diastolic blood pressure with an increased risk of morbidity. Initial misdiagnosis occurred in 17.1% of cases, with the majority of those misdiagnosed (83.3%) aged less than 2 years. Predominant serotyping was Group B followed by Group C. Major findings were a marked male preponderance in patients under 3 months of age. The incidence of meningococcal infection in the Aboriginal population was approximately six times that in the non-Aboriginal population. The yearly incidence of meningococcal disease during the study period ranged from 5.2 to 10.5 per 100,000. Long-term morbidity occurred in 8.6% of cases and mortality was 8.6%. Higher morbidity and mortality figures were found in those with septicaemia alone. Children referred from peripheral hospitals had a higher mortality but a comparable morbidity.

Age Distribution↗
PubMed1999

Antepartum fetal and maternal carboxyhemoglobin and cotinine levels among cigarette smokers.

The objective of this study was to examine the association of carboxyhemoglobin (COHb) and plasma cotinine levels among pregnant women who smoke cigarettes and their fetuses. Fifteen pregnant women who smoked and their fetuses undergoing cordocentesis had blood samples analysed simultaneously for COHb and cotinine. Linear regression was used to test for associations among study variables. Significant maternal-fetal associations were observed both with COHb (r = 0.72, p = 0.003) and with cotinine (r = 0.96, p = 0.003). Maternal cotinine levels were correlated with maternal and fetal COHb levels (r = 0.96, p = 0.003; r = 0.99, p = 0.0003, respectively). Fetal cotinine levels were correlated with COHb in maternal and in fetal blood (r = 0.81, p = 0.0003; r = 0.88, p<0.0001, respectively). The strong direct associations of maternal and fetal levels of COHb and cotinine indicate that maternal COHb and cotinine measurements may be interpreted as surrogates of fetal COHb levels. However, the specificity, ex vivo stability and ease of measurement of cotinine offer advantages over using COHb in quantifying fetal CO exposure following maternal cigarette smoking.

Adult↗
PubMed1998

Screening of maternal serum for fetal Down's syndrome in the first trimester.

BACKGROUND: Screening of maternal serum to identify fetuses with Down's syndrome is now routinely offered during the second trimester of pregnancy. Prenatal screening by means of serum assays or ultrasonographic measurements, either alone or in combination, may also be possible in the first trimester. METHODS: We measured serum alpha-fetoprotein, unconjugated estriol, human chorionic gonadotropin (hCG), the free beta subunit of hCG, and pregnancy-associated protein A in 4412 women (82 percent of whom were 35 years of age or older) who came to 16 prenatal diagnostic centers for chorionic-villus sampling or early amniocentesis at 9 to 15 weeks of gestation. Ultrasound measurements of fetal nuchal translucency were also reported. Fetal chromosomal analysis was performed in all pregnancies. Altogether, there were 61 fetuses with Down's syndrome. RESULTS: A total of 48 pregnancies affected by Down's syndrome and 3169 unaffected pregnancies were identified before 14 weeks of gestation; the rates of detection of Down's syndrome for the five serum markers were as follows: 17 percent for alpha-fetoprotein, 4 percent for unconjugated estriol, 29 percent for hCG, 25 percent for the free beta subunit of hCG, and 42 percent for pregnancy-associated protein A, at false positive rates of 5 percent. The results of the measurements of serum hCG and its free beta subunit were highly correlated. When used in combination with the serum concentration of pregnancy-associated protein A and maternal age, the detection rate was 63 percent for hCG (95 percent confidence interval, 47 to 76 percent) and 60 percent for its free beta subunit (95 percent confidence interval, 45 to 74 percent). Measurements of nuchal translucency varied considerably between centers and could not be reliably incorporated into our calculations. CONCLUSIONS: Screening for Down's syndrome in the first trimester is feasible, with use of measurements of pregnancy-associated protein A and either hCG or its free beta subunit in maternal serum.

Adolescent↗
PubMed1998

Screening for Down syndrome at 14 weeks of pregnancy.

To investigate whether statistical parameters used in Down syndrome screening between 15 and 22 weeks of pregnancy can be used at 14 weeks, we assayed alpha-fetoprotein (AFP), unconjugated oestriol (uE3), total human chorionic gonadotrophin (hCG), free alpha-hCG, free beta-hCG, and inhibin-A in 16 pregnancies with Down syndrome in the 14th week of pregnancy and expressed values in multiples of the normal median. The median and standard deviation values for these 16 pregnancies were not materially different from those published for 15-22 weeks. It is reasonable, therefore, to offer Down syndrome screening using these markers starting at 14 completed weeks of pregnancy instead of 15 weeks. It needs to be recognized, however, that serum AFP measurement for neural tube defect screening is less effective at this time than between 16 and 18 weeks of pregnancy.

Chorionic Gonadotropin↗
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↗
PubMed1997

Maternal serum screening for Down syndrome in the United States: a 1995 survey.

OBJECTIVE: Our goal was to determine the status of prenatal Down syndrome screening in the United States in 1995. STUDY DESIGN: Information was sought via questionnaire from laboratories participating in external proficiency testing. RESULTS: Services were provided to 2,498,000 women annually by 265 screening laboratories. All but 10 laboratories offered both open neural tube defect and Down syndrome screening. Twenty-one percent of Down syndrome interpretations were based on alpha-fetoprotein measurements alone; 79% also included other serum analytes. Sixty-six laboratories (26%) offered interpretations at 14 weeks' gestation or earlier. CONCLUSIONS: Some laboratories extend serum screening too early in gestation for optimal neural tube defect interpretation. When 1995 was compared with 1992, more women were being screened, a higher proportion were receiving a Down syndrome interpretation, and more interpretations were based on multiple analytes. Laboratories should be encouraged to use some combination of multiple markers when screening for Down syndrome.

Amniotic Fluid↗
PubMed1996

Quality assessment of a prenatal screening program.

Epidemiologic monitoring is a process which uses data generated from the screened population as a quality control measure. Most commonly, laboratories monitor the percentage of women with screen positive test results, i.e., with test results falling at or above a specified multiple of the median (MoM) for open neural tube defect screening or, with a risk at or above a specified risk cut-off for Down's syndrome screening. These percentages are sensitive to inaccurate and imprecise assays, inappropriate reference data, and long term assay drift. In fetal Down's syndrome screening it is necessary to simultaneously monitor two or more assays, which is accomplished by monitoring the median MoM for each assay (which should be 1.0 within statistical limits) calculated using patient MoM values. Monitoring the median MoM can identify inappropriate adjustment factors for variables which affect the MoM such as maternal weight. Epidemiologic monitoring is a useful tool for identifying problems which are not readily apparent using traditional quality control measures.

Down Syndrome↗
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↗
PubMed1996

Refinements in managing maternal weight adjustment for interpreting prenatal screening results.

This study examines the relationship between maternal weight and serum levels of alpha-fetoprotein, unconjugated oestriol, and human chorionic gonadotropin in a population of 47,585 women being provided with prenatal screening for Down's syndrome and open neural tube defects. The study population contains sufficient numbers of women at the extremes of weight to allow the determination that a reciprocal-linear equation more accurately describes the weight relationship for two of the three analytes than the currently used log-linear equations. The reciprocal-linear equations, while more appropriate, provide only a minimal advantage over the log-linear equations. A more important finding is that published weight equations may not be optimal for some screening programmes, due to differences in the mean weight of the populations being tested. Screening programmes are encouraged to calculate their own weight correction formulae, based on data from their own population, and to monitor the mean maternal weight to detect when modifications in the weight correction formulae might be indicated.

Body Weight↗
PubMed1995

Risk-based prenatal screening for trisomy 18 using alpha-fetoprotein, unconjugated oestriol and human chorionic gonadotropin.

Nine centres collaborated to examine the feasibility of a screening method for trisomy 18 that was based on assigning individual risk, using a combination of maternal age and measurements of alpha-fetoprotein (AFP), unconjugated oestriol (uE3), and human chorionic gonadotropin (hCG). Second-trimester measurements of these analytes were obtained from 94 trisomy 18 pregnancies. In the 89 pregnancies without an associated open defect, the median levels for AFP, uE3, and hCG were 0.65, 0.43 and 0.36 multiples of the unaffected population median, respectively. The strongest individual predictor of risk for trisomy 18 was uE3, followed by hCG, AFP, and maternal age, in that order. Using a method of individual risk estimation that is based on the three markers and maternal age, 60 per cent of pregnancies associated with trisomy 18 would be detected at a risk cut-off level of 1:100, with a false-positive rate of about 0.2 per cent. One in nine pregnancies identified as being at increased risk for trisomy 18 would be expected to have an affected pregnancy. This risk-based screening method is more efficient than an existing method that is based on fixed analyte cut-off levels. Even though the birth prevalence of trisomy 18 is low, prenatal screening can be justified when performed in conjunction with Down syndrome screening and when a high proportion of women offered amniocentesis have an affected fetus.

Adult↗