Gunhild Garmo Hov

Risk assessment for preeclampsia in nulliparous women at 11–13 weeks gestational age: prospective evaluation of two algorithms

To evaluate two algorithms for prediction of preeclampsia in a population of nulliparous women in Norway.

A prospective study of screening for hypertensive disorders of pregnancy at 11-13 weeks in a Scandinavian population.

To investigate the prediction of preeclampsia and gestational hypertension using maternal characteristics, mean arterial pressure (MAP), uterine artery pulsatility index (UtAPI), pregnancy‐associated plasma protein‐A (PAPP‐A) and placental growth factor (PlGF) at gestational weeks 11–13 in a Scandinavian population with a medium to high prior risk for developing hypertensive disorders of pregnancy.

Arginine/asymmetric dimethylarginine ratio and cardiovascular risk factors in patients with predialytic chronic kidney disease

OBJECTIVES Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase (NOS) that accumulates in patients with chronic kidney disease (CKD) and predicts cardiovascular outcome. Arginine is the substrate for NOS and a low arginine/ADMA ratio may lead to a reduced NO production and a worse prognosis. We have studied how other important CKD variables predict the arginine/ADMA ratio. DESIGN AND METHODS The population is 160 predialytic CKD patients (median age 61 years). We used backward stepwise regression to identify the best predictors of p-arginine, p-ADMA and arginine/ADMA ratio. RESULTS P-ADMA was predicted by estimated GFR (eGFR) (adjusted R(2)=0.17, p>0.00). Arginine/ADMA ratio was predicted by gender, eGFR, use of renin angiotensin aldosteron (RAAS) inhibitors, current smoking and use of platelet inhibitors (adjusted R(2)=0.18, p<0.00). CONCLUSIONS Reduced eGFR is associated with reduced arginine/ADMA ratio. The use of RAAS inhibitors and male gender may be protective against a low arginine/ADMA ratio.

Arginine, dimethylated arginine and homoarginine in relation to cardiovascular risk in patients with moderate chronic kidney disease

OBJECTIVES Arginine, asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), arginine/ADMA ratio and homoarginine could potentially affect nitric oxide production and have been studied in relation to cardiovascular risk (CVR) in various clinical populations. Prospective studies on the CVR associated with arginine/ADMA ratio and homoarginine in patients with moderate chronic kidney disease (CKD) are still scarce. We have studied how arginine, homoarginine and dimethylated arginine can predict cardiovascular events in such a population. DESIGN AND METHODS We measured plasma concentrations of arginine (P-arginine), ADMA (P-ADMA), SDMA (P-SDMA), homoarginine (P-homoarginine) and other covariates in 160 patients with predialytic CKD (mean age 57 years and mean eGFR 43 mL/min/1.73 m(2)) and followed them for 58 months in median. The risks of fatal and non-fatal cardiovascular events associated with the predictors were evaluated with multivariable Cox proportional hazard analysis. RESULTS There were 31 cardiovascular events during the observation period. In a multivariable model adjusted for age, sex, previous cardiovascular disease, P-cystatin C and P-homoarginine, the hazard ratio (HR) associated with an increase in arginine/ADMA ratio by 10 was 0.83 (P=0.03). The HR of a 1 μmol/L increase in P-homoarginine in the same model was 1.78 (P=0.01). A statistically significant interaction between P-homoarginine and P-cystatin C was found in an extended multivariable model. P-SDMA was not associated with increased CVR after adjustment for basic covariates. CONCLUSION This study demonstrates a negative association between arginine/ADMA ratio and CVR in CKD patients and a positive association between P-homoarginine and CVR. The latter is in contrast to what has been demonstrated by others.

Using probit regression to disclose the analytical performance of qualitative and semi-quantitative tests

Abstract Background: The analytical performance of qualitative and semi-quantitative tests is usually studied by calculating the fraction of positive results after replicate testing of a few specimens with known concentrations of the analyte. We propose using probit regression to model the probability of positive results as a function of the analyte concentration, based on testing many specimens once with a qualitative and a quantitative test. Methods: We collected laboratory data where urine specimens had been analyzed by both a urine albumin (‘protein’) dipstick test (Combur-Test strips) and a quantitative test (BN ProSpec System). For each dipstick cut-off level probit regression was used to estimate the probability of positive results as a function of urine albumin concentration. We also used probit regression to estimate the standard deviation of the continuous measurement signal that lies behind the binary test response. Finally, we used probit regression to estimate the probability of reading a specific semi-quantitative dipstick result as a function of urine albumin concentration. Results: Based on analyses of 3259 specimens, the concentration of urine albumin with a 0.5 (50%) probability of positive result was 57 mg/L at the lowest possible cut-off limit, and 246 and 750 mg/L at the next (higher) levels. The corresponding standard deviations were 29, 83, and 217 mg/L, respectively. Semi-quantitatively, the maximum probability of these three readings occurred at a u-albumin of 117, 420, and 1200 mg/L, respectively. Conclusions: Probit regression is a useful tool to study the analytical performance of qualitative and semi-quantitative tests.

Reference limits for chromogranin A, CYFRA 21-1, CA 125, CA 19-9 and carcinoembryonic antigen in patients with chronic kidney disease

Background Patients with chronic kidney disease (CKD) may have increased plasma concentrations of some tumor markers even when no cancer is present. Previous studies have indicated that plasma concentrations of chromogranin A (CGA), cytokeratin 19 fragments (CYFRA 21-1), cancer antigen 125 (CA 125), cancer antigen 19-9 (CA 19-9) and carcinoembryonic antigen (CEA) are higher in patients with CKD but without cancer, than in healthy individuals, and this can make interpretation of results more complicated. The aim of this study was to establish reference limits for these markers in patients with CKD not receiving dialysis and with no clinical evidence of cancer. Methods We measured plasma concentrations in samples from 131 patients with CKD due to various etiologies and studied the association of tumor marker concentrations with estimated glomerular filtration rate (GFR) and other patient characteristics. Results Estimated reference limits for plasma CA 125, CA 19-9 and CEA were approximately the same as for healthy populations. Serum concentrations of CGA and CYFRA 21-1 correlated strongly with estimated GFR, and GFR-dependent reference limits were estimated. Conclusions GFR-dependent reference limits for CGA and CYFRA 21-1 are reported in order to support interpretation of these markers in patients with CKD.

Using the hazard ratio to evaluate allowable total error in predictive measurands

Abstract Background: Allowable total error is usually derived from data on biological variation or from state-of-the-art of measuring technology. Here we present a new principle for evaluating allowable total error when the concentration of the analyte (the measurand) is used for prediction: What are the predictive consequences of allowable total errors in terms of errors in the estimate of the hazard ratio (HR)? Methods: We explored the effect of analytical measurement errors on Cox regression estimates of HR. Published data on Cox regression coefficients were used to illustrate the effect of measurement errors on predicting cardiovascular events or death based on serum concentration of cholesterol and on progression of chronic kidney disease to kidney failure based on serum concentrations of albumin, bicarbonate, calcium and phosphate, and urine albumin/creatinine-ratio. Results: If the acceptable error in the estimate of the HR is 10%, allowable total errors in serum cholesterol, bicarbonate and phosphate are approximately the same as allowable total error based on biological variation, while allowable total error in serum albumin and calcium are a little larger than estimates based on biological variation. Conclusions: Evaluating allowable total error from its effect on the estimate of HR is universally applicable to measurands used for prediction.

Are age-specific reference ranges for CYFRA 21-1 appropriate?

We have read the paper by Zhao et al. [1] who estimated reference limits for the tumor marker CYFRA 21-1 in healthy Chinese adults. We question some of their conclusions. Zhao et al. measured CYFRA 21-1 in serum samples from almost 10,000 healthy Chinese Han ethnic adults and estimated upper reference limits for men and women at different age intervals. They excluded individuals with diseases that might influence the serum concentration of CYFRA 21-1, including those with chronic renal failure defined as glomerular filtration rate (GFR) persistently below 15ml/min per 1.73m. The mean age was 48.9 years, the age range was 18–95 years and 66.7% of the reference individuals were men. They estimated an overall upper reference limit of 4.47 mg/L, corresponding to the 95th percentile of the distribution of CYFRA among all included individuals. As the concentration of CYFRA 21-1 correlated with sex and age, they estimated sexand age-specific upper reference limits, ranging from 3.65mg/L in women aged 18 to 39 years to 6.02 mg/L in women 80 years or older. For all age intervals, they estimated higher limits than recommended by the provider of the analytical method used (Roche Diagnostics GmbH), which is 3.3 mg/L, according to the authors. Although impressive with respect to sample size, we believe that the presented conclusions have some significant flaws. First; the authors do not describe the renal function in the reference individuals, except that those with GFR <15ml/min/1.73m were excluded. Several studies have demonstrated increased serum concentrations of CYFRA 21-1 in individuals with impaired renal function [2–8]. We studied the distribution of CYFRA in patients with kidney disease and no evident cancer [8]. They had estimated GFR (eGFR) between 12 and 133ml/min/1.73m. Serum concentrations of CYFRA 21-1 correlated with eGFR, and in patients with eGFR <60ml/min/1.73m the 95th percentile was 4.4 mg/L. In patients with eGFR 60ml/min/1.73m, it was 2.1 mg/L. Accordingly, in order to interpret the results from the study by Zhao et al., the prevalence of impaired GFR, preferably also the distribution of GFR, should be described in their reference sample group. Secondly, they conclude that age-specific limits for CYFRA should be estimated. This is in contrast with the results of our study. We observed no statistically significant dependence of the 95th percentile of CYFRA 21-1 on sex or age when eGFR was part of a quantile regression model with eGFR, sex and age as predictor variables. However, the 95th percentile significantly depended on eGFR. It is well known that GFR tends to decrease with increasing age, but the upper reference limit appeared in our study to be much more dependent on eGFR than sex and age. Although our study was small compared to the study by Zhao et al., it does not support their conclusion that ageand sex-specific limits should be applied, unless these factors affect the GFRadjusted 95th percentile. Third, they conclude that serum concentrations of CYFRA 21-1 is higher in Chinese Han adults than in the western white population. As discussed above, we believe that they cannot conclude in this way without having estimated reference limits in individuals with normal GFR. We encourage the authors to re-examine their data, including the 119 outliers that were eliminated and publish the GFR distribution in their reference sample group. We also believe that they should estimate reference limits among the individuals with GFR higher and lower than, for example, 60ml/min/1.73 m, or they could estimate GFRdependent reference limits, as we did [8]. Without this information, we believe that it is not possible to interpret the results of their study.