Individual Patient-specific Risks Research Articles

Impulse control disorders in Parkinson’s disease: a national Swedish registry study on high-risk treatments and vulnerable patient groups

BackgroundImpulse control disorders (ICDs) are known psychiatric conditions in Parkinson’s disease (PD), especially as a side effect of antiparkinsonian therapy. Screening for vulnerable patients and avoiding high-risk treatments can be...

Ophthalmic artery Doppler at 36 weeks' gestation in prediction of pre-eclampsia: validation and update of previous model.

To validate and extend a model incorporating maternal ophthalmic artery Doppler at 35-37 weeks' gestation in the prediction of subsequent development of pre-eclampsia (PE). This was a prospective validation study of screening for PE (defined according to the 2019 American College of Obstetricians and Gynecologists criteria) by maternal ophthalmic artery peak systolic velocity (PSV) ratio in 6746 singleton pregnancies undergoing routine care at 35 + 0 to 36 + 6 weeks' gestation (validation dataset). Additionally, the data from the validation dataset were combined with those of 2287 pregnancies that were previously used for development of the model (training dataset), and the combined data were used to update the original model parameters. The competing-risks model was used to estimate the individual patient-specific risk of delivery with PE at any time and within 3 weeks from assessment by a combination of maternal demographic characteristics and medical history with PSV ratio alone and in combination with the established PE biomarkers of mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI), serum placental growth factor (PlGF) and serum soluble fms-like tyrosine kinase-1 (sFlt-1). We evaluated the predictive performance of the model by examining, first, the ability to discriminate between the PE and non-PE groups using the area under the receiver-operating-characteristics curve and the detection rate (DR) at fixed screen-positive (SPR) and false-positive rates of 10% and, second, calibration by measuring the calibration slope and calibration-in-the-large. McNemar's test was used to compare the performance of screening by a biophysical test (maternal factors, MAP, UtA-PI and PSV ratio) vs a biochemical test (maternal factors, PlGF and sFlt-1), low PlGF concentration (< 10th percentile) or high sFlt-1/PlGF concentration ratio (> 90th percentile). In the validation dataset, the performance of screening by maternal factors and PSV ratio for delivery with PE within 3 weeks and at any time after assessment was consistent with that in the training dataset, and there was good agreement between the predicted and observed incidence of PE. In the combined data from the training and validation datasets, good prediction for PE was achieved in screening by a combination of maternal factors, MAP, UtA-PI, PlGF, sFlt-1 and PSV ratio, with a DR, at a 10% SPR, of 85.0% (95% CI, 76.5-91.4%) for delivery with PE within 3 weeks and 65.7% (95% CI, 59.2-71.7%) for delivery with PE at any time after assessment. The performance of a biophysical test was superior to that of screening by low PlGF concentration or high sFlt-1/PlGF concentration ratio but not significantly different from the performance of a biochemical test combining maternal factors with PlGF and sFlt-1 for both PE within 3 weeks and PE at any time after assessment. Maternal ophthalmic artery PSV ratio at 35-37 weeks' gestation in combination with other biomarkers provides effective prediction of subsequent development of PE. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Machine learning predictive model for lumbar disc reherniation following microsurgical discectomy

IntroductionThe integration of machine learning (ML) algorithms into the field of neurosurgery has the potential to facilitate the decision-making process for the surgeons, improve the surgical outcomes and the overall patient satisfaction rates. Reoperations for same level lumbar disc reherniation are associated with poorer outcomes and greater rate of complications. Research questionProper preoperative patient evaluation could reveal the individuals at higher risk of reherniation. A novel machine learning algorithm was used for the creation of a predictive scoring system for lumbar disc reherniation for patients requiring microdiscectomy without fusion. Material and methodsRetrospective chart review was completed of all adult patients that underwent microdiscectomy without fusion for symptomatic single level LDH, in a single center, over the last 3 years. 230 patients met the inclusion criteria. 19 of them required a second surgical intervention due to same level reherniation. ResultsUtilizing the Risk-SLIM model, the Lumbar Reherniation Score (LRS) was created. The score's accuracy was tested against other model architectures, and a standard five-fold cross-validation was performed. The LRS has AUC of 0.87, confusion matrix accuracy of 0.74, Matthews correlation coefficient of 0.36 and informedness of 0.62. The LRS individual reherniation risk probability ranges from 0% to 88.1%. Discussion and conclusionThe LRS is a novel, easy-to-use, patient-specific tool for preoperative prediction of the individual patient-specific risk of same level symptomatic reherniation following microdiscectomy. Further validation and testing of the model is needed before it can be used in real-life patient treatment.

Risk and benefits of baseline antiplatelet therapy in 58,598 patients with atrial fibrillation randomized to NOACs vs warfarin

Abstract Background The efficacy and safety of NOAC versus warfarin (W) may differ in AF pts receiving antiplatelet therapy (APT) at baseline. Moreover, prior individual trial-specific analyses examining the treatment effect of NOAC vs. W as a function of APT are underpowered for interaction testing. Purpose We evaluated outcomes by randomized anticoagulant stratified by baseline APT in a pooled individual pt-level meta-analysis of 4 pivotal RCTs of NOAC vs. W in AF: RE-LY, ROCKET-AF, ARISTOTLE, and ENGAGE AF-TIMI 48. Methods Pts were stratified by use of APT vs. no APT at baseline. Pts randomized to low-dose NOAC not globally approved (edoxaban 30/15 mg or dabigatran 110 mg) were excluded. The primary efficacy and safety outcomes were stroke/systemic embolic events (S/SEE) and major bleeding, respectively; ischemic stroke (IS), intracranial hemorrhage (ICH), major GI bleeding and all-cause mortality (ACM) were secondary outcomes. Each outcome was assessed by randomized treatment using a Cox model stratified by trial with adjustment for age, sex, weight, CrCl, smoking status, HTN, DM, CAD, prior MI, PAD, and prior stroke. Interaction testing was performed by APT at baseline. Results Of 58,598 pts, 19,774 (34%) were on APT at baseline (92% aspirin only, 5% P2Y12 only, 3% DAPT). Pts treated with APT had greater prevalence of CAD (41% vs. 24%), prior MI (22% vs. 11%), and PAD (6% vs. 4%) (p&amp;lt;0.001 for each). Reflective of these baseline differences, the annualized event rate for each outcome was higher in the APT vs. no APT group (Figure). The treatment effect (HR) of NOAC vs. W for all 6 clinical outcomes was consistent irrespective of baseline APT (p-interaction [aHR] for each = NS; Figure). However, the absolute risk reduction (ARR) for NOAC vs. W differed for ICH and major GI bleeding as a function of baseline APT (Figure). Specifically, for ICH, a greater absolute benefit was seen with NOAC vs. W in those on APT at baseline (ARR 0.6% vs. 0.3%; p-int = 0.007). Conversely, for major GI bleeding, NOAC vs. W was associated with greater absolute risk in those on APT (ARR -0.6% vs. -0.2%; p-int = 0.04). Conclusions The treatment effect of NOAC vs. W is consistent irrespective of APT at baseline for S/SEE, major bleeding, and ACM. Given higher rates of bleeding in AF pts treated with both APT and anticoagulation, concomitant APT should be avoided when possible. In pts requiring concomitant APT, NOAC instead of W should be considered owing to greater absolute safety benefit for ICH, which should be weighed against individual patient-specific risk factors for GI bleeding.

Ophthalmic artery Doppler at 11-13 weeks' gestation in prediction of pre-eclampsia.

To examine the potential value of maternal ophthalmic artery Doppler at 11-13 weeks' gestation, alone and in combination with the established first-trimester biomarkers of pre-eclampsia (PE), including uterine artery pulsatility index (UtA-PI), mean arterial pressure (MAP), serum placental growth factor (PlGF) and serum pregnancy-associated plasma protein-A (PAPP-A), in the prediction of subsequent development of PE. This was a prospective observational study in women attending for a routine hospital visit at 11 + 0 to 13 + 6 weeks' gestation. This visit included recording of maternal demographic characteristics and medical history, ultrasound examination for fetal anatomy and growth, assessment of flow velocity waveforms from the maternal ophthalmic arteries and calculation of the second-to-first peak systolic velocity (PSV) ratio, and measurement of MAP and serum PAPP-A. In addition, a case-control study was carried out for measurement of PlGF in stored samples from cases that developed PE and unaffected controls. The values of PSV ratio, UtA-PI, MAP, PAPP-A and PlGF were converted to multiples of the median or deltas to remove the effects of maternal characteristics and medical history. The competing-risks model was used to estimate the individual patient-specific risk of delivery with PE at < 37 and < 41 + 3 weeks' gestation for various combinations of markers. Performance was assessed using detection rates, at a fixed false-positive rate (FPR), and areas under the receiver-operating-characteristics curves. Modeled performance was also assessed. The study population of 4066 pregnancies contained 114 (2.8%) that developed PE, including 25 (0.6%) that delivered with PE at < 37 weeks' gestation. The PSV ratio was significantly increased in PE pregnancies, and the effect of PE depended on gestational age at delivery, with the deviation from normal being greater for early than for late PE. Modeling demonstrated that the addition of PSV ratio improved the detection rate, at a 10% FPR, of preterm PE provided by maternal risk factors alone (from 46.3% to 58.4%), maternal factors, MAP and UtA-PI (65.9% to 70.6%), and maternal factors, MAP, UtA-PI and PlGF (74.6% to 76.7%). The PSV ratio did not improve the prediction of term PE provided by any combination of biomarkers. Ophthalmic artery PSV ratio at 11-13 weeks' gestation is a potentially useful biomarker for prediction of subsequent development of preterm PE, but larger studies are needed to validate this finding. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Osteitis/Osteomyelitis of the Hand and Wrist

Osteomyelitis of the hand and wrist is uncommon compared to the infections of the long bones but not rare. There is poor evidence on many answers to questions concerning this disease. This includes careful consideration of the prevalence, pathogenesis, microbiology, diagnostic methods and the conservative, medical and surgical treatment. The emergence of the disease can subdivided in post-traumatic, postoperative, spread from contiguous infections and hematogenous. The individual patient-specific risk must be considered. Early diagnosis and correct management are essential to preserve bony structures and the articular function of the hand. A two-step surgical procedure is usually necessary, but uncertainties about the optimal treatment are still existing. Satisfactory control rates of the infection and successful bone reconstructions can be achieved. But complications, a limited range of motion and amputations of finger parts can still not be avoided in all cases.

Maternal cardiac function at 19-23 weeks' gestation in prediction of pre-eclampsia.

First, to examine the factors from maternal characteristics and medical history that affect maternal cardiovascular indices, and, second, to examine the potential value of maternal cardiovascular indices at 19-23 weeks' gestation, on their own and in combination with maternal factors and the established biomarkers of pre-eclampsia (PE), including uterine artery pulsatility index (UtA-PI), mean arterial pressure (MAP), serum placental growth factor (PlGF) and serum soluble fms-like tyrosine kinase-1 (sFlt-1), in the prediction of subsequent development of PE. This was a prospective observational study in women attending for a routine hospital visit at 19 + 1 to 23 + 3 weeks' gestation. This visit included recording of maternal demographic characteristics and medical history, assessment of maternal E/A ratio, E/e' ratio, myocardial performance index, global longitudinal systolic strain, left ventricular ejection fraction, peripheral vascular resistance, left ventricular cardiac output and left ventricular mass indexed for body surface area, and measurement of MAP, UtA-PI, serum PlGF and serum sFlt-1. The measurements of the eight maternal cardiac indices were standardized to remove the effects of maternal characteristics and elements from the medical history. The competing-risks model was used to estimate the individual patient-specific risks of delivery with PE and determine the detection rate, at a 10% false-positive rate, in screening by a combination of maternal demographic characteristics and medical history with biomarkers. The study population of 2853 pregnancies contained 76 (2.7%) that developed PE. In pregnancies that subsequently developed PE, there was evidence of altered cardiac geometry, impaired myocardial function and increased peripheral vascular resistance. All maternal cardiovascular indices were affected significantly by maternal demographic characteristics and elements of medical history known to be associated with an increased risk for subsequent development of PE. After adjustment for maternal demographic characteristics and medical history, the only cardiovascular index that was affected significantly by subsequent development of PE was peripheral vascular resistance. Peripheral vascular resistance multiples of the median (MoM) was correlated with MAP MoM, which is not surprising because blood pressure is involved in the estimation of both. There were weak correlations between several cardiovascular indices and MAP MoM, but none was correlated with MoM values of UtA-PI, PlGF or sFlt-1. The performance of screening for delivery with PE at < 37 weeks' gestation or delivery with PE at any gestational age in screening by maternal demographic characteristics and medical history or combinations of maternal factors with MAP, UtA-PI, PlGF and sFlt-1 was not improved by the addition of peripheral vascular resistance. Assessment of maternal cardiovascular function provides information on the pathophysiology of PE but is not useful in the prediction of PE. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Ophthalmic artery Doppler in combination with other biomarkers in prediction of pre-eclampsia at 35-37 weeks' gestation.

To examine the potential value of maternal ophthalmic artery Doppler at 35-37 weeks' gestation in combination with the established biomarkers of pre-eclampsia (PE), including mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI), serum placental growth factor (PlGF) and serum soluble fms-like tyrosine kinase-1 (sFlt-1), in the prediction of subsequent development of PE. This was a prospective observational study in women attending for a routine hospital visit at 35 + 0 to 36 + 6 weeks' gestation. This visit included recording of maternal demographic characteristics and medical history, ultrasound examination for fetal anatomy and growth, assessment of flow velocity waveforms from the maternal ophthalmic arteries, and measurement of MAP, UtA-PI, serum PlGF and serum sFlt-1. The competing-risks model was used to estimate the individual patient-specific risks of delivery with PE at any time and at < 3 weeks after assessment by a combination of maternal demographic characteristics and medical history with biomarkers. The area under the receiver-operating-characteristics curve and detection rate (DR) of delivery with PE, at a 10% false-positive rate (FPR), in screening by combinations of maternal factors with ophthalmic artery second to first peak of systolic velocity ratio (PSV ratio), MAP, UtA-PI, serum PlGF and serum sFlt-1 were determined. The modeled performance of screening for PE was also estimated. The study population of 2287 pregnancies contained 60 (2.6%) that developed PE, including 19 (0.8%) that delivered with PE at < 3 weeks after assessment. The PSV ratio improved the prediction of PE with delivery at any stage after assessment provided by maternal factors alone (from 25.4% to 50.6%), maternal factors and MAP (54.3% to 62.7%), maternal factors, MAP and PlGF (68.3% to 70.8%) and maternal factors, MAP, PlGF and sFlt-1 (75.7% to 76.7%), at a FPR of 10%. The PSV ratio also improved the prediction of PE with delivery at < 3 weeks after assessment provided by maternal factors alone (from 31.0% to 69.4%), maternal factors and MAP (74.1% to 83.4%), maternal factors, MAP and UtA-PI (77.1% to 85.0%) and maternal factors, MAP and PlGF (84.8% to 88.6%). The empirical results for DR at a 10% FPR were consistent with the modeled results. Screening by a combination of maternal factors with MAP and PSV ratio also detected 59.4% (95% CI, 58.6-82.5%) of cases of gestational hypertension with delivery at any stage after assessment, and 86.7% (95% CI, 82.4-100%) of those with delivery at < 3 weeks after assessment. Ophthalmic artery Doppler could potentially improve the performance of screening for PE at 35-37 weeks, especially imminent PE with delivery within 3 weeks after assessment, but further studies are needed to validate this finding. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Ophthalmic artery Doppler in combination with other biomarkers in prediction of pre-eclampsia at 19-23 weeks' gestation.

To examine the potential value of maternal ophthalmic artery Doppler at 19-23 weeks' gestation on its own and in combination with the established biomarkers of pre-eclampsia (PE), including uterine artery (UtA) pulsatility index (PI), mean arterial pressure (MAP), serum placental growth factor (PlGF) and serum soluble fms-like tyrosine kinase-1 (sFlt-1), in the prediction of subsequent development of PE. This was a prospective observational study of women attending for a routine hospital visit at 19 + 1 to 23 + 3 weeks' gestation. This visit included recording of maternal demographic characteristics and medical history, ultrasound examination for fetal anatomy and growth, assessment of flow velocity waveforms from the maternal ophthalmic arteries, and measurement of MAP, UtA-PI, serum PlGF and serum sFlt-1. Waveforms were obtained from the ophthalmic arteries in sequence from the right eye, left eye and again from the right and then left eye. We recorded the average of the four measurements, two from each eye, for the following four indices: first peak of systolic velocity; second peak of systolic velocity; PI; and the ratio of the second to first peak of systolic velocity (PSV ratio). The measurements of the four indices were standardized to remove the effects of maternal characteristics and elements from the medical history. The competing-risks model was used to estimate the individual patient-specific risks of delivery with PE at < 37 and ≥ 37 weeks' gestation and to determine the area under the receiver-operating-characteristics curve (AUC) and detection rate (DR), at a 10% false-positive rate (FPR), in screening by a combination of maternal demographic characteristics and medical history with biomarkers. The modeled performance of screening for PE was also estimated. The study population of 2853 pregnancies contained 76 (2.7%) that developed PE, including 18 (0.6%) that delivered with PE at < 37 weeks' gestation. The ophthalmic artery PSV ratio was significantly increased in PE pregnancies, and the PE effect depended on gestational age at delivery; the deviation from normal was greater for early than late PE. The second peak of systolic velocity was also increased in PE pregnancies, but the effect did not depend on gestational age at delivery. The other two ophthalmic artery indices of first peak of systolic velocity and PI were not significantly affected by PE. The PSV ratio improved the prediction of preterm PE provided by maternal factors alone (from 56.1% to 80.2%), maternal factors, MAP and UtA-PI (80.7% to 87.9%), maternal factors, MAP, UtA-PI and PlGF (85.5% to 90.3%) and maternal factors, MAP, UtA-PI, PlGF and sFlt-1 (84.9% to 89.8%), at a FPR of 10%. The PSV ratio also improved the prediction of term PE provided by maternal factors alone (from 33.8% to 46.0%), maternal factors, MAP and UtA-PI (46.6% to 54.2%), maternal factors, MAP, UtA-PI and PlGF (45.2% to 53.4%) and maternal factors, MAP, UtA-PI, PlGF and sFlt-1 (43.0% to 51.2%), at a FPR of 10%. The empirical results for DR at a 10% FPR were consistent with the modeled results. The second peak of systolic velocity did not improve the prediction of either preterm or term PE provided by maternal factors alone. Ophthalmic artery PSV ratio at 19-23 weeks' gestation, both on its own and in combination with other biomarkers, is potentially useful for prediction of subsequent development of PE, especially preterm PE, but larger studies are needed to validate this finding. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Predictive performance of the competing risk model in screening for preeclampsia

The established method of screening for preeclampsia is to identify risk factors from maternal demographic characteristics and medical history; in the presence of such factors the patient is classified as high risk and in their absence as low risk. However, the performance of such an approach is poor. We developed a competing risks model, which allows combination of maternal factors (age, weight, height, race, parity, personal and family history of preeclampsia, chronic hypertension, diabetes mellitus, systemic lupus erythematosus or antiphospholipid syndrome, method of conception and interpregnancy interval), with biomarkers to estimate the individual patient-specific risks of preeclampsia requiring delivery before any specified gestation. The performance of this approach is by far superior to that of the risk scoring systems. The objective of the study was to examine the predictive performance of the competing risks model in screening for preeclampsia by a combination of maternal factors, mean arterial pressure, uterine artery pulsatility index, and serum placental growth factor, referred to as the triple test, in a training data set for the development of the model and 2 validation studies. The data for this study were derived from 3 previously reported prospective, nonintervention, multicenter screening studies for preeclampsia in singleton pregnancies at 11+0 to 13+6 weeks' gestation. In all 3 studies, there was recording of maternal factors and biomarkers and ascertainment of outcome by appropriately trained personnel. The first study of 35,948 women, which was carried out between February 2010 and July 2014, was used to develop the competing risks model for prediction of preeclampsia and is therefore considered to be the training set. The 2 validation studies were comprised of 8775 and 16,451 women, respectively, and they were carried out between February and September 2015 and between April and December 2016, respectively. Patient-specific risks of delivery with preeclampsia at <34, <37, and <41+3 weeks' gestation were calculated using the competing risks model and the performance of screening for preeclampsia by maternal factors alone and the triple test in each of the 3 data sets was assessed. We examined the predictive performance of the model by first, the ability of the model to discriminate between the preeclampsia and no-preeclampsia groups using the area under the receiver operating characteristic curve and the detection rate at fixed screen-positive rate of 10%, and second, calibration by measurements of calibration slope and calibration in the large. The detection rate at the screen-positive rate of 10% of early-preeclampsia, preterm-preeclampsia, and all-preeclampsia was about 90%, 75%, and 50%, respectively, and the results were consistent between the training and 2 validation data sets. The area under the receiver operating characteristic curve was >0.95, >0.90, and >0.80, respectively, demonstrating a very high discrimination between affected and unaffected pregnancies. Similarly, the calibration slopes were very close to 1.0, demonstrating a good agreement between the predicted risks and observed incidence of preeclampsia. In the prediction of early-preeclampsia and preterm-preeclampsia, the observed incidence in the training set and 1 of the validation data sets was consistent with the predicted one. In the other validation data set, which was specifically designed for evaluation of the model, the incidence was higher than predicted, presumably because of better ascertainment of outcome. The incidence of all-preeclampsia was lower than predicted in all 3 data sets because at term many pregnancies deliver for reasons other than preeclampsia, and therefore, pregnancies considered to be at high risk for preeclampsia that deliver for other reasons before they develop preeclampsia can be wrongly considered to be false positives. The competing risks model provides an effective and reproducible method for first-trimester prediction of early preeclampsia and preterm preeclampsia as long as the various components of screening are carried out by appropriately trained and audited practitioners. Early prediction of preterm preeclampsia is beneficial because treatment of the high-risk group with aspirin is highly effective in the prevention of the disease.

Prediction of individual combined benefit and harm for patients with atrial fibrillation considering warfarin therapy: a study protocol

IntroductionClinical prediction rules have been validated and widely used in patients with atrial fibrillation (AF) to predict stroke and major bleeding. However, these prediction rules were not developed in the...

First-Trimester Screening for Trisomy 21 with Adjustment for Biochemical Results of Previous Pregnancies

Objective: To investigate the effect of associations in serum free β-hCG and PAPP-A between successive pregnancies on the performance of screening for trisomy 21 at 11–13 weeks’ gestation. Methods: In 8,499 women with two consecutive pregnancies, including 49 women with fetal trisomy 21 in the second pregnancy, the correlation in serum free β-hCG multiples of the median (MoM) and PAPP-A MoM between pregnancies was determined, and the effects of correcting for the correlation on the performance of screening was estimated. Results: There were significant associations between pregnancies in free β-hCG MoM (r = 0.4435) and PAPP-A MoM (r = 0.4796). In screening by maternal age and biochemistry at a risk cutoff of 1 in 100, in the second pregnancies the false-positive rate was 35.5% for those with screen-positive results in the first pregnancy, and this was reduced to 17.1% after adjustment for the results of the first pregnancy. Similarly, in women with screen-negative results in the first pregnancy, adjustment for the results improved the detection rate in the second pregnancy from 66.7 to 81.2%. Conclusions: In screening for trisomy 21, adjustment for the biochemical findings in a previous pregnancy has major effects on individual patient-specific risks, increases the detection rate and reduces the false-positive rate.

Managing the risks of immunosuppression

New immunomodulating approaches to neuroinflammatory diseases present new challenges in clinical risk management. We review recent data on immunosuppression in diverse settings to guide the assessment and prevention of adverse effects from these therapies with the aim of improving the benefit to risk equation. Although individual immunomodulatory agents affect the immune system in different ways, there are common themes in patient risk. Impairment of immunity is primarily responsible for an increased risk of a characteristic spectrum of infection-related cancers in immunocompromised patients. Additional themes include the reactivation of existing infections such as herpes viruses, mycobacterial and JC virus infections, vaccine preventable disease, cardiovascular and metabolic risk and immune dysregulation resulting in autoimmune and immune reconstitution inflammatory syndromes. An online immunosuppression screening tool may help reduce omissions in individual patient-specific risk assessment. Systematic patient-tailored risk management protocols will be required to ensure reduction in preventable adverse outcomes with new immunomodifying approaches to neuroinflammatory disease and thereby optimize the benefits to patients from these treatments.

Dose dependency between cigarette consumption and reduced maternal serum PAPP‐A levels at 11–13+6 weeks of gestation

To examine whether in smokers there is a significant dose dependency between the number of cigarettes per day and levels of free ss-hCG and pregnancy-associated plasma protein A (PAPP-A) at 11-13(+6) weeks of gestation. This was a retrospective analysis of the maternal serum free ss-hCG and PAPP-A levels in relation to the maternal smoking status in 109 263 chromosomally normal singleton pregnancies that had undergone first-trimester screening for Down syndrome by a combination of fetal nuchal translucency thickness and maternal serum biochemistry. There were 95 287 nonsmokers and 13 976 cigarette smokers. The overall median PAPP-A MoM among cigarette smokers was 0.827, which was 19.6% lower than the value of 1.029 in nonsmokers (p < 0.0001 for log(10) MoM). The respective values for beta-hCG MoM were 1.003 for smokers and 1.035 for nonsmokers (p < 0.0001 for log(10) MoM) which corresponds to a reduction of 3.1%. There was a significant inverse relationship between the number of cigarettes per day and the level of PAPP-A MoM (r = 0.989, p < 0.0001) but not the level of free beta-hCG MoM (r = 0.733; p = 0.098). Using a statistical modeling approach we found that the screen-positive rate when correcting the PAPP-A MoM by an all or nil smoking factor was reduced by only 0.1% (3.75 vs 3.85%) when compared to correcting with a factor related to the smoking dose per day. In first-trimester screening for Down syndrome by maternal serum PAPP-A and free beta-hCG the impact of correcting for the dose dependant rather than the all or nil effect of smoking is marginal. However, a dose dependent correction improves the accuracy of the individual patient-specific risk.

The impact of correcting for smoking status when screening for chromosomal anomalies using maternal serum biochemistry and fetal nuchal translucency thickness in the first trimester of pregnancy.

To evaluate the influence of cigarette smoking status on maternal serum free beta-hCG, PAPP-A and fetal nuchal translucency (NT) thickness at 11 to 14 weeks of gestation in a large cohort of women screened prospectively for chromosomal anomalies. Information on maternal cigarette smoking status, maternal age, maternal serum biochemical marker levels and fetal NT were collected from the prenatal screening computer records in two OSCAR screening centres. Data was available from 32,730 unaffected pregnancies and from 124 with Down syndrome. Statistical analysis of the marker levels in the smoking and non-smoking group were carried out. The impact on false-positive rate of correcting for smoking status was assessed from a modelling exercise. Prevalence of smoking was significantly affected by maternal age with an overall incidence of 11.5%, which varied from 35% in women under 20 to 7% in women over 35. In the unaffected population, the median free beta-hCG MoM was significantly lower in the smoking group (0.97 vs 1.00) as was that for PAPP-A (0.84 vs 1.02). The standard deviation of the log(10) MoM free beta-hCG was lower in the smoking group and that for PAPP-A was higher in the smoking group. The difference in median marker levels did not seem to be related to the number of cigarettes smoked per day. In the group with Down syndrome, the median MoM free beta-hCG was not significantly different in the smokers (1.69 vs 1.86) as was that for PAPP-A (0.53 vs 0.57). Fetal delta NT was not significantly different in the unaffected smokers (0.11 vs 0.0 mm) or in those with Down syndrome (1.96 vs 2.25 mm). In the smoking group, when screening using maternal serum biochemistry and age alone, the false-positive rate was 6.17%, compared to 4.67% in an age-matched group of non-smokers. Correcting for smoking status by dividing the measured MoM by the median found in the smoking group resulted in the false-positive rate falling to 4.40%. When screening using NT, maternal serum biochemistry and age, the false-positive rate in smokers was 4.48%, which reduced to 3.46% after correction-in line with the 3.76% in the non-smoking group. The impact on detection rate was too small to be accurately measured. The impact of smoking on first-trimester biochemical marker levels does not seem to be dose related. Whilst correcting first-trimester biochemical markers for maternal smoking status has little impact at the population level for detection rates, a considerable reduction in false-positive rate can be achieved, reducing the level to that seen in non-smokers. However, the effect on the individual patient-specific risk can be substantial and could certainly make a difference to the patient's decision on whether to have an invasive test.

Maternal weight correction of maternal serum PAPP‐A and free β‐hCG MoM when screening for trisomy 21 in the first trimester of pregnancy

To assess the suitability of either the log-linear or reciprocal-linear regression procedure for maternal weight correction of biochemical marker MoMs in the first trimester. Data from two prospective first-trimester OSCAR screening programmes including 32,010 women with first-trimester maternal serum-free beta-hCG and PAPP-A measured by the Kryptor analyser was analysed by regression analysis to provide parameters for the log-linear and reciprocal-linear MoM correction procedures. Assessment was made by goodness of fit to the data. The impact on detection rate and false-positive rate of the different correction procedures was assessed using statistical modelling with biochemical markers alone. Both log-linear and reciprocal-linear correction were shown to fit the data well. For free beta-hCG, the log-linear procedure was marginally superior to the reciprocal-linear procedure (r2=0.986 v 0.980), whilst for PAPP-A the reciprocal-linear procedure was marginally better (r2=0.991 v 0.985). Log-linear correction reduced the variance for both markers more than did the reciprocal-linear procedure. For free beta-hCG, the sd was reduced from 0.2675 to 0.2605 and for PAPP-A, it was reduced from 0.2545 to 0.2336. Correcting for maternal weight was shown to reduce the population false-positive rate from 7.0 to 6.5%, whilst maintaining the same detection rate at a risk cut-off of 1 in a 100. At individual levels, a two-fold variation in risk was demonstrated depending upon the individual's weight. To provide accurate individual patient-specific risks for trisomy 21, maternal weight must be taken into account and should be a mandatory data item for screening programmes. Maternal weight correction in the first trimester using free beta-hCG and PAPP-A can be best achieved using the log-linear procedure.

Delta-NT or NT MoM: which is the most appropriate method for calculating accurate patient-specific risks for trisomy 21 in the first trimester?

To assess whether in screening for trisomy 21 by nuchal translucency (NT) the delta or the multiples of the median (MoM) approach is the most appropriate method for calculating accurate individual patient-specific risks. Data on fetal NT and crown-rump length from 128,030 unaffected and 428 trisomy 21 pregnancies, measured by sonographers who had obtained The Fetal Medicine Foundation Certificate of Competence in the 11-14-Week Scan, were used. We examined first, if the distribution of NT MoM and log(10)(NT MoM) was Gaussian; second, if the standard deviation of the distributions did not change with gestation; and third, if the median MoM in the affected population was a constant proportion of the median for unaffected pregnancies. All of these features are required to underpin the MoM approach. NT distributions and those of delta-NT were also analyzed. A non-parametric kernel density method was then used to assess the validity of both methods. Errors in the estimation of individual patient-specific risks using the MoM approach were assessed. In the unaffected pregnancies, the distributions of NT MoM and log(10)(NT MoM) were not Gaussian and the standard deviation of log(10)(NT MoM) decreased with gestation. In the trisomy 21 pregnancies, the median NT MoM decreased significantly with gestation, whereas the median delta-NT did not change with gestation. The non-parametric density approach showed that contours of constant likelihood ratio were parallel to the gestational age-dependent median NT values, thus supporting the delta-NT approach. The NT MoM approach resulted in women being given an overestimate of risk for trisomy at 11 weeks and a considerable underestimate of risk at 13 weeks. In the calculation of risk for trisomy 21 by NT the NT MoM approach is inaccurate and inappropriate because the underlying assumptions are not valid. In contrast, the delta-NT approach gives accurate estimates of risks.

The effect of temporal variation in biochemical markers of trisomy 21 across the first and second trimesters of pregnancy on the estimation of individual patient-specific risks and detection rates for Down's syndrome.

In a previous study we examined the changes in the median multiple of the median (MoM) with gestation of free beta human chorionic gonadotrophin (F beta-hCG), total human chorionic gonadotrophin (ThCG), alpha-fetoprotein (AFP) and pregnancy-associated plasma protein A (PAPP-A) in a large series of Down's syndrome pregnancies. Results showed that there was a significant temporal variation of the MoM for each marker. In this paper, we assess the impact of this temporal shift on the estimation of patient-specific risks and the detection rates (DRs) for Down's syndrome pregnancies. Individual patient-specific risks, DRs and false positive rates were estimated using statistical modelling techniques and computer simulations. The data for these simulations were the regressed mean log(10) analyte MoMs, marker standard deviations (as log(10) MoM) and correlation coefficients derived from the analysis of over 1000 cases of Down's syndrome and 150,000 unaffected pregnancies between 6 and 20 weeks of gestation reported in our previous study. Two models were compared: the classical constant median separation model, which assumes no variation in median shift with gestation (model 1), and a variable median separation model (model 2), which takes account of the changes in median shift with gestation as described in our previous study. When individual patient-specific risks calculated for various MoM values using model 1 were compared with those derived from model 2, considerable differences in risk estimates were observed for all marker combinations, particularly in the first trimester. Using a 1 in 250 cut-off risk, DRs at each gestation in the second trimester for the AFP+F beta-hCG combination were maximized at 14-17 weeks of gestation and were virtually identical at 63-65% for model 1 and model 2. A similar trend was observed for the AFP+ThCG combination, with an optimum gestational range of 15-18 weeks and DRs of 66-68%. In the first trimester, using a 1 in 250 cut-off risk, DRs were more variable with gestation for the prime marker combination of F beta-hCG+PAPP-A, varying from 73% at 8 weeks to 65% at 13 weeks with model 1 and from 75% to 66% with model 2. Risk algorithms should take into account temporal variation in marker MoMs in order to produce accurate patient-specific risks. This also helps to maximize DRs, particularly when samples are taken out with the optimal gestational range.