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Biomedical subjects

G E Palomaki

Publications and source records attributed to G E Palomaki.

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↗
PubMed2003

Cystic fibrosis: selecting the prenatal screening strategy of choice.

Cystic fibrosis is a serious disorder. Research into the treatment of affected individuals is in progress, but a cure is not expected in the near future. In this review, we demonstrate that prenatal screening for cystic fibrosis meets the requirements for a worthwhile screening programme. We explain the reasons that have led us to conclude that one approach ('couple screening') is the method of choice. The couple-based approach calls for reporting results to the couple as a unit. Only if both parents are found to be carriers is the result designated screen-positive and an amniocentesis or chorionic villus sampling offered. This offers a substantial reduction in the proportion of women with unaffected pregnancies with positive results (the false-positive rate) compared with other methods without reducing the detection of affected pregnancies. It also avoids creating a screen-positive group for which no definitive diagnosis is available. This is a problem with other screening methods. The couple method can achieve a 72% detection rate for a 0.1% false-positive rate. The screening method is simple, non-invasive, reliable, safe and reasonably cost effective. Existing programmes have shown that screening using this method is acceptable to health care professionals and patients. Setting up a national prenatal screening programme for cystic fibrosis is timely and should be implemented using the couple screening method.

Adult↗
PubMed2003

Hereditary haemochromatosis and hepatocellular carcinoma in males: a strategy for estimating the potential for primary prevention.

OBJECTIVES: Homozygosity for the C282Y mutation of the HFE gene is the main cause of iron overload in hereditary haemochromatosis. This study calculated the number of hepatocellular carcinoma cases among a cohort of white males that could be attributed to C282Y homozygosity. A better understanding of the extent of potentially preventable mortality arising from this cancer might help with decision making about the feasibility of population screening. METHODS: We combined information from published life tables, age-specific cancer rates and DNA studies of archived liver biopsy specimens to calculate the number of cases of hepatocellular carcinoma that might occur during the lifetime of a cohort of 1,000,000 men, including a subgroup of 5000 C282Y homozygotes. RESULTS: Hepatocellular carcinoma was estimated to occur in 2673 men in the cohort (1:374); 267 of these cases were in the subgroup of 5000 C282Y homozygotes (1:17). If these 267 cases were prevented, the remaining lifetime risk among all males would be 1:416. The relative risk for this cancer in C282Y homozygotes is 23. CONCLUSIONS: There continues to be uncertainty about the efficacy of screening for haemochromatosis. Hepatocellular carcinoma is the most readily quantifiable serious health problem attributable to this source. Further confirmatory DNA (C282Y) studies would be helpful in larger, unbiased sets of archived biopsy specimens, as a way to confirm the present estimate. Any strategy designed to prevent attributable liver cancer is likely to prevent other serious problems from haemochromatasis as well.

Adult↗
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↗
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↗
PubMed2001

An evaluation of analytic goals for assays of drugs: a College of American Pathologists Therapeutic Drug Monitoring Survey Study.

OBJECTIVE: To determine if the levels of imprecision of the commonly used analytic methods for drug measurements are suitable for long-term therapeutic drug monitoring. DESIGN: In 1996, 4 identical lyophilized samples (2 in the first mailing and 2 in the second mailing 4 months later) were sent to laboratories participating in a nationwide proficiency testing program. Similarly, in 1999, replicates from a liquid pool of spiked sera were mailed 3 times, 4 months apart, to participating laboratories. For each of 11 drugs regulated under the Clinical Laboratory Improvement Amendments of 1988 and 1 metabolite, the total variance for each method was partitioned into within- and between-laboratory components. The total within-laboratory and the total survey coefficients of variation (CVs) for each method were then compared with the "acceptable" precision criteria of Glick, Burnett, and Fraser for each drug. SETTING: The first 2 mailings of the College of American Pathologists Therapeutic Drug Monitoring surveys for 1996, sets Z and ZM, and the 3 mailings of 1999, sets ZM, Z, and Z2. MAIN OUTCOME MEASURES: For each drug studied, the CV of each method was compared with the various imprecision criteria, and if greater than any of the criteria, the method was then tabulated as not meeting that specific criterion.Participants.-The approximately 5000 participants of the survey. RESULTS: The number of methods deemed as not having acceptable total long-term within-laboratory precision by the various criteria ranged from 35% to 88% in 1996 and from 22% to 77% in 1999. CONCLUSION: The number of failures possibly indicates that many of the reagent assays being utilized are not precise enough for long-term therapeutic drug monitoring of chronically administered drugs or that the published criteria used to evaluate the data in this study are too stringent.

Data Collection↗
PubMed2000

Second trimester levels of maternal serum inhibin A in pregnancies affected by fetal neural tube defects.

Inhibin A is effective as a second trimester maternal serum marker for Down syndrome screening. In the present study, inhibin A levels were measured in second trimester maternal serum samples from 28 pregnancies affected with open neural tube defects; 12 associated with open spina bifida and 16 associated with anencephaly. Each measurement was expressed as a multiple of the median (MoM) for control singleton pregnancies (n=1464) of the same completed week of gestation. Inhibin A levels were not significantly altered in cases of open neural tube defects; the median value was 0.96 MoM in cases of open spina bifida and 1.19 MoM in cases of anencephaly. Therefore, second trimester maternal serum inhibin A levels will not have an impact on prenatal detection of open neural tube defects.

Anencephaly↗
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

Maternal thyroid deficiency and pregnancy complications: implications for population screening.

OBJECTIVE: To examine the relation between certain pregnancy complications and thyroid stimulating hormone (TSH) measurements in a cohort of pregnant women. METHODS: TSH was measured in sera obtained from women during the second trimester as part of routine prenatal care. Information was then collected about vaginal bleeding, premature delivery, low birthweight, abruptio placentae, pregnancy induced hypertension, need for cesarean section, low Apgar scores, and fetal and neonatal death. RESULTS: Among 9403 women with singleton pregnancies, TSH measurements were 6 mU/l or greater in 209 (2.2%). The rate of fetal death was significantly higher in those pregnancies (3.8%) than in the women with TSH less than 6 mU/l (0.9%, odds ratio 4.4, 95% confidence interval 1.9-9.5). Other pregnancy complications did not occur more frequently. CONCLUSION: From the second trimester onward, the major adverse obstetrical outcome associated with raised TSH in the general population is an increased rate of fetal death. If thyroid replacement treatment avoided this problem this would be another reason to consider population screening.

Adult↗
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

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↗