Sharing ICU Patient Data Responsibly Under the Society of Critical Care Medicine/European Society of Intensive Care Medicine Joint Data Science Collaboration: The Amsterdam University Medical Centers Database (AmsterdamUMCdb) Example.

OBJECTIVES: Critical care medicine is a natural environment for machine learning approaches to improve outcomes for critically ill patients as admissions to ICUs generate vast amounts of data. However, technical, legal, ethical, and privacy concerns have so far limited the critical care medicine community from making these data readily available. The Society of Critical Care Medicine and the European Society of Intensive Care Medicine have identified ICU patient data sharing as one of the priorities under their Joint Data Science Collaboration. To encourage ICUs worldwide to share their patient data responsibly, we now describe the development and release of Amsterdam University Medical Centers Database (AmsterdamUMCdb), the first freely available critical care database in full compliance with privacy laws from both the United States and Europe, as an example of the feasibility of sharing complex critical care data. SETTING: University hospital ICU. SUBJECTS: Data from ICU patients admitted between 2003 and 2016. INTERVENTIONS: We used a risk-based deidentification strategy to maintain data utility while preserving privacy. In addition, we implemented contractual and governance processes, and a communication strategy. Patient organizations, supporting hospitals, and experts on ethics and privacy audited these processes and the database. MEASUREMENTS AND MAIN RESULTS: AmsterdamUMCdb contains approximately 1 billion clinical data points from 23,106 admissions of 20,109 patients. The privacy audit concluded that reidentification is not reasonably likely, and AmsterdamUMCdb can therefore be considered as anonymous information, both in the context of the U.S. Health Insurance Portability and Accountability Act and the European General Data Protection Regulation. The ethics audit concluded that responsible data sharing imposes minimal burden, whereas the potential benefit is tremendous. CONCLUSIONS: Technical, legal, ethical, and privacy challenges related to responsible data sharing can be addressed using a multidisciplinary approach. A risk-based deidentification strategy, that complies with both U.S. and European privacy regulations, should be the preferred approach to releasing ICU patient data. This supports the shared Society of Critical Care Medicine and European Society of Intensive Care Medicine vision to improve critical care outcomes through scientific inquiry of vast and combined ICU datasets.

Challenges and Opportunities for Cancer Predisposition Cascade Screening for Hereditary Breast and Ovarian Cancer and Lynch Syndrome in Switzerland: Findings from an International Workshop.

BACKGROUND: An international workshop on cancer predisposition cascade genetic screening for hereditary breast and ovarian cancer (HBOC) and Lynch syndrome (LS) took place in Switzerland, with leading researchers and clinicians in cascade screening and hereditary cancer from different disciplines. The purpose of the workshop was to enhance the implementation of cascade genetic screening in Switzerland. Participants discussed the challenges and opportunities associated with cascade screening for HBOC and LS in Switzerland (CASCADE study); family implications and the need for family-based interventions; the need to evaluate the cost-effectiveness of cascade genetic screening; and interprofessional collaboration needed to lead this initiative. METHODS: The workshop aims were achieved through exchange of data and experiences from successful cascade screening programs in the Netherlands, Australia, and the state of Ohio, USA; Swiss-based studies and scientific experience that support cancer cascade screening in Switzerland; programs of research in psychosocial oncology and family-based studies; data from previous cost-effectiveness analyses of cascade genetic screening in the Netherlands and in Australia; and organizational experience from a large interprofessional collaborative. Scientific presentations were recorded and discussions were synthesized to present the workshop findings. RESULTS: The key elements of successful implementation of cascade genetic screening are a supportive network of stakeholders and connection to complementary initiatives; sample size and recruitment of relatives; centralized organization of services; data-based cost-effectiveness analyses; transparent organization of the initiative; and continuous funding. CONCLUSIONS: This paper describes the processes and key findings of an international workshop on cancer predisposition cascade screening, which will guide the CASCADE study in Switzerland.

The Relationship of Metabolic Syndrome Traits with Beta-Cell Function and Insulin Sensitivity by Oral Minimal Model Assessment in South Asian and European Families Residing in the Netherlands.

Background. There are different metabolic syndrome traits among patients with different ethnicities. Methods. We investigated this by studying 44 South Asians and 54 Europeans and classified them in three groups according to the occurrence of metabolic syndrome (MetS) and Type 2 Diabetes (T2D). Insulin sensitivity index (ISI), static, dynamic, and total beta-cell responsivity indices (Φ), and disposition indices (DIs) were calculated with the use of oral minimal model (OMM). Results. In both ethnicities, ISI was lower in the subgroup with MetS and T2D as compared to the subgroup without MetS nor T2D (P < 0.004). South Asians without MetS were more insulin resistant than Europeans without MetS (P = 0.033). In the South Asians, ISI, dynamic DI, and static DI were associated significantly (P < 0.006) with high-density lipoprotein cholesterol and triglycerides. In the Europeans, ISI was associated with waist-to-hip ratio (P = 0.005) and systolic and diastolic blood pressure (P < 0.005), while static DI was related to the systolic blood pressure (P = 0.005). Conclusions. MetS was linked with insulin resistance and reduced capacity to handle glucose regardless of ethnicity. ISI and DIs were associated with lipid traits in South Asians and with blood pressure in Europeans suggesting that insulin resistance enhances different metabolic syndrome traits among different ethnicities.

A stable isotope method for in vivo assessment of human insulin synthesis and secretion.

AIMS: In vitro, beta cells immediately secrete stored but readily releasable insulin in response to a rise of glucose. During a prolonged insulin response, this is followed by newly synthesized insulin. Our aim was to develop an in vivo test to determine the ratio between readily available and newly synthesized insulin after a stimulus in humans by labelling newly synthesized insulin. METHODS: A stable isotope tracer of 1.0 g 13C leucine with C-peptide as target peptide was administered 45 min prior to 75 g glucose load of a frequently blood sampled 210-min oral glucose tolerance test (OGTT). Our OGTT also encompassed collection of urine, which has a high content of C-peptide. Prior, the optimal conditions under which the tracer 13C leucine was administered for enrichment of (pre) proinsulin were established. Also, techniques to obtain urinary C-peptide under highly purified circumstances were set up. Our main outcome measure was the stable isotope enrichment of de novo C-peptide, which we related to early plasma insulin and glucose AUC. Twelve healthy Caucasian individuals (M4F8, age 41.8 ± 2.3, BMI 28.3 ± 1.7) with normal glucose tolerance underwent our OGTT. RESULTS: We found that during a 75-g OGTT, newly synthesized insulin contributed approximately 20 % of total insulin secretion. The pattern of isotope enrichment obtained by collecting multiple urine voids was suggestive that the newly synthesized insulin contributes to the late phase of insulin secretion. De novo C-peptide correlated negatively with both early plasma insulin AUC (r = -0.629, P = 0.028) and early plasma glucose AUC (r = -0.605, P = 0.037). CONCLUSIONS: With stable isotope technique added to OGTT, we were able to measure newly synthesized insulin in healthy individuals. This new technique holds the promise that it is feasible to develop a direct in vivo beta cell function test.

Cascade screening based on genetic testing is cost-effective: evidence for the implementation of models of care for familial hypercholesterolemia.

BACKGROUND: Familial hypercholesterolemia (FH) imposes significant burden of premature coronary heart disease (CHD). OBJECTIVE: This study aimed to determine the cost-effectiveness of FH detection based on genetic testing, supplemented with the measurement of plasma low-density lipoprotein cholesterol concentration, and treatment with statins. METHODS: A Markov model with a 10-year time horizon was constructed to simulate the onset of first-ever CHD and death in close relatives of probands with genetically confirmed FH. The model comprised of 3 health states: "alive without CHD," "alive with CHD," and "dead." Decision-analysis compared the clinical consequences and costs of cascade-screening vs no-screening from an Australian health care perspective. The annual risk of CHD and benefits of treatment was estimated from a cohort study. The underlying prevalence of FH, sensitivity, specificity, cost of screening, treatment, and clinic follow-up visits were derived from a cascade screening service for FH in Western Australia. An annual discount rate of 5% was applied to costs and benefits. RESULTS: The model estimated that screening for FH would reduce the 10-year incidence of CHD from 50.0% to 25.0% among people with FH. Of every 100 people screened, there was an overall gain of 24.95 life-years and 29.07 quality-adjusted life years (discounted). The incremental cost-effectiveness ratio was in Australian dollars, $4155 per years of life saved and $3565 per quality-adjusted life years gained. CONCLUSION: This analysis within an Australian context, demonstrates that cascade screening for FH, using genetic testing supplemented with the measurement of plasma low-density lipoprotein cholesterol concentrations and treatment with statins, is a cost-effective means of preventing CHD in families at risk of FH.

Assessment of carotid atherosclerosis, intraplaque neovascularization, and plaque ulceration using quantitative contrast-enhanced ultrasound in asymptomatic patients with diabetes mellitus.

AIMS: Patients with diabetes mellitus (DM) are at severely increased risk of developing atherosclerosis. Intraplaque neovascularization (IPN) and plaque ulceration are markers of the vulnerable plaque, which is at an increased risk of rupture and may lead to cardiovascular events. The aim of this study was to assess the prevalence of subclinical carotid atherosclerosis, intraplaque neovascularization (IPN), and plaque ulceration in asymptomatic patients with DM. METHODS AND RESULTS: A total of 51 asymptomatic patients with DM underwent standard carotid ultrasound in conjunction with contrast-enhanced ultrasound (CEUS) to assess the prevalence of subclinical atherosclerosis, IPN, and plaque ulceration. Subclinical atherosclerosis was defined as the presence of atherosclerotic plaque, according to the Mannheim consensus. Semi-automated quantification software was used to assess IPN in suitable plaques. Plaque ulceration was defined as a disruption of the plaque-lumen border of ≥ 1 × 1 mm. A total of 408 carotid segments in 102 carotid arteries were investigated. Forty-six (90%) patients had subclinical atherosclerotic plaques, with a median plaque thickness of 2.4 mm (inter-quartile range 1.9-3.0). CEUS revealed IPN in 88% of the patients. In 10 carotid segments (8%), the plaque had an ulcerated surface. The presence of IPN could not be predicted by the presence of clinical characteristics including complications of DM (P > 0.05). CONCLUSION: Patients with DM have a high prevalence (90%) of subclinical carotid atherosclerosis. Severe IPN and plaque ulceration, which are markers of the vulnerable plaque type, were detected in, respectively, 13 and 9% of these patients.

Integrated guidance on the care of familial hypercholesterolemia from the International FH Foundation.

Familial hypercholesterolemia (FH) is a dominantly inherited disorder present from birth that markedly elevates plasma low-density lipoprotein cholesterol and causes premature coronary heart disease. There are at least 20 million people with FH worldwide, but the majority remains undetected, and current treatment is often suboptimal. To address this major gap in coronary prevention we present, from an international perspective, consensus-based guidance on the care of FH. The guidance was generated from seminars and workshops held at an international symposium. The recommendations focus on the detection, diagnosis, assessment, and management of FH in adults and children and set guidelines for clinical purposes. They also refer to best practice for cascade screening and risk notifying and testing families for FH, including use of genetic testing. Guidance on treatment is based on risk stratification, management of noncholesterol risk factors, and the safe and effective use of low-density lipoprotein-lowering therapies. Recommendations are given on lipoprotein apheresis. The use of emerging therapies for FH is also foreshadowed. This international guidance acknowledges evidence gaps but aims to make the best use of contemporary practice and technology to achieve the best outcomes for the care of FH. It should accordingly be used to inform clinical judgment and be adjusted for country-specific and local healthcare needs and resources.

Integrated guidance on the care of familial hypercholesterolaemia from the International FH Foundation.

Familial hypercholesterolaemia (FH) is a dominantly inherited disorder present from birth that markedly elevates plasma low-density lipoprotein (LDL) cholesterol and causes premature coronary heart disease. There are at least 20 million people with FH worldwide, but the majority remain undetected and current treatment is often suboptimal. To address this major gap in coronary prevention we present, from an international perspective, consensus-based guidance on the care of FH. The guidance was generated from seminars and workshops held at an international symposium. The recommendations focus on the detection, diagnosis, assessment and management of FH in adults and children, and set guidelines for clinical purposes. They also refer to best practice for cascade screening and risk notifying and testing families for FH, including use of genetic testing. Guidance on treatment is based on risk stratification, management of non-cholesterol risk factors, and safe and effective use of LDL lowering therapies. Recommendations are given on lipoprotein apheresis. The use of emerging therapies for FH is also foreshadowed. This international guidance acknowledges evidence gaps, but aims to make the best use of contemporary practice and technology to achieve the best outcomes for the care of FH. It should accordingly be employed to inform clinical judgement and be adjusted for country-specific and local health care needs and resources.

Utility of contrast-enhanced ultrasound for the assessment of the carotid artery wall in patients with Takayasu or giant cell arteritis.

AIMS: Carotid contrast-enhanced ultrasound (CEUS) was recently proposed for the evaluation of large-vessel vasculitides (LVV), particularly to assess vascularization within the vessel wall. The aim of this pilot study was to evaluate the potential of carotid colour Doppler ultrasound (CDUS) and CEUS in patients with LVV. METHODS AND RESULTS: This prospective study included seven patients (mean age 48 ± 14 years, all females) with established LVV (Takayasu arteritis or giant cell arteritis). All patients underwent CDUS and CEUS (14 carotid arteries). Intima-media thickness, lumen diameter, Doppler velocities, vessel wall thickening, and lesion thickness were assessed. CEUS was used to improve visualization of the lumen-to-vessel wall border, and to visualize carotid wall vascularization. Four (57%) patients [7 (50%) carotid arteries] exhibited lesions, and the average lesion thickness was 2.0 ± 0.5 mm. According to the Doppler peak systolic velocity, 5 (35%) carotid arteries had a <50% stenosis, 1 (7%) had a 50-70% stenosis, and 1 (7%) had a ≥70% stenosis. The contrast agent improved the image quality and the definition of the lumen-to-vascular wall border. Carotid wall vascularization was observed in 5 (71%) patients [9 (64%) carotid arteries]. Five (36%) carotid arteries had mild-to-moderate vascularization, and 4 (29%) had severe wall vascularization. CONCLUSION: Carotid CDUS allows the assessment of anatomical features of LVV, including vessel wall thickening and degree of stenosis. Carotid CEUS improves the visualization of the lumen border, and allows dynamic assessment of carotid wall vascularization, which is a potential marker of disease activity in patients with LVV.

Assessment of subclinical atherosclerosis and intraplaque neovascularization using quantitative contrast-enhanced ultrasound in patients with familial hypercholesterolemia.

OBJECTIVE: Patients with heterozygous familial hypercholesterolemia (FH) are at severely increased risk of developing atherosclerosis at relatively young age. The aim of this study was to assess the prevalence of subclinical atherosclerosis and intraplaque neovascularization (IPN) in patients with FH, using contrast-enhanced ultrasound (CEUS) of the carotid arteries. METHODS: The study population consisted of 69 consecutive asymptomatic patients with FH (48% women, mean age 55 ± 8 years). All patients underwent carotid ultrasound to evaluate the presence and severity of carotid atherosclerosis, and CEUS to assess IPN. IPN was assessed in near wall plaques using a semi-quantitative grading scale and semi-automated quantification software. RESULTS: Carotid plaque was present in 62 patients (90%). A total of 49 patients had plaques that were eligible for the assessment of IPN: 7 patients (14%) had no IPN, 39 (80%) had mild to moderate IPN and 3 (6%) had severe IPN. Semi-automated quantification software showed no statistical significant difference in the amount of IPN between patients > 50 years and patients ≤ 50 years and between patients with a defective low-density lipoprotein receptor (LDLR) mutation and patients with a negative LDLR mutation. Plaques with irregular or ulcerated surface had significantly more IPN than plaques with a smooth surface (p < 0.05). CONCLUSION: Carotid ultrasound demonstrated atherosclerotic plaque in 90% of asymptomatic patients with FH without known atherosclerosis. IPN assessed with CEUS, was present in 86% of these patients. Irregular and ulcerated plaques exhibited significantly more IPN than plaques with a smooth surface.

Carotid intima-media thickness for cardiovascular risk assessment: systematic review and meta-analysis.

OBJECTIVE: B-mode ultrasound measurement of the carotid intima-media thickness (CIMT) is a widely used marker for atherosclerosis and is associated with future cardiovascular events. This article provides a review and meta-analysis of the published evidence on the association of CIMT with future cardiovascular events and its additional value to traditional cardiovascular risk prediction models. METHODS: A systematic review and meta-analysis of the evidence on the association of CIMT with future cardiovascular events and the additional value of CIMT to traditional cardiovascular risk prediction models was conducted. The association of CIMT with future cardiovascular events and the additional value of CIMT were calculated using random effects analysis. RESULTS: The literature search yielded 1196 articles of which 15 articles provided sufficient data for the meta-analysis. A 1 SD increase in CIMT was predictive for myocardial infarction (HR 1.26, 95% CI 1.20-1.31) and for stroke (HR 1.31, 95% CI 1.26-1.36). A 0.1 mm increase in CIMT was predictive for myocardial infarction (HR 1.15, 95% CI 1.12-1.18) and for stroke (HR 1.17, 95% CI 1.15-1.21). The overall performance of risk prediction models did not significantly increase after addition of CIMT data. The areas under the curve increased from 0.726 to 0.729 (p = 0.8). CONCLUSIONS: CIMT as measured by B-mode ultrasound is associated with future cardiovascular events. However, the addition of CIMT to traditional cardiovascular risk prediction models does not lead to a statistical significantly increase in performance of those models.

Assessment of subclinical atherosclerosis using contrast-enhanced ultrasound.

AIMS: The sensitivity of standard carotid ultrasound and colour Doppler for the detection of subclinical atherosclerotic plaques is suboptimal. The aim of this study is to assess whether contrast-enhanced ultrasound (CEUS) added to standard carotid ultrasound improves the detection of subclinical atherosclerosis. METHODS AND RESULTS: Carotid intima-media thickness (CIMT) measurement, standard carotid ultrasound including colour Doppler imaging, and CEUS were performed in 100 asymptomatic patients with one or more risk factors for atherosclerosis. CEUS was performed using intravenous administration of SonoVue™ contrast agent (Bracco S.p.A., Milan, Italy). CIMT, standard ultrasound, colour Doppler, and CEUS were reviewed by two independent observers. Standard ultrasound, colour Doppler, and CEUS were scored for the presence of atherosclerotic plaques. Subclinical atherosclerosis was diagnosed if patients had a CIMT above their age-corrected threshold value or if atherosclerotic plaques were present on standard carotid ultrasound clips or CEUS clips. McNemar's test was performed to compare between groups. Twenty-one patients (21%) had a thickened CIMT value and were considered to have subclinical atherosclerosis. Standard carotid ultrasound including colour Doppler demonstrated atherosclerotic plaques in 77 patients (77%). The addition of CEUS to the standard ultrasound protocol demonstrated atherosclerotic plaques in 88 patients (88%). The incorporation of CEUS into the standard carotid ultrasound protocol resulted in a significantly improved detection of patients with subclinical atherosclerosis (P < 0.01). CONCLUSION: CEUS has an incremental value for the detection of subclinical atherosclerosis in the carotid arteries. Atherosclerotic plaques which were only detected with CEUS and not with standard carotid ultrasound and colour Doppler imaging were predominantly hypoechoic.

The Prevention Of WEight Regain in diabetes type 2 (POWER) study: the effectiveness of adding a combined psychological intervention to a very low calorie diet, design and pilot data of a randomized controlled trial.

BACKGROUND: Obesity is of major pathogenetic importance to type 2 diabetes, it contributes to poor glycemic control and increases the risk of cardiovascular disease. Over 80% of patients with diabetes type 2 are overweight. To achieve a more favourable risk profile, changes in diet and lifestyle are needed. However, current treatment programs for obese DM type 2 patients are not effective in the long term. In this RCT, we compare the effectiveness of a Combined Psychological Intervention (CPI) and usual care in maintaining the favourable effects on weight and risk profile during 2 years of follow-up after a Very Low Calorie Diet (VLCD). METHODS AND DESIGN: In a randomised parallel group intervention study, 140 patients with type 2 diabetes and overweight (BMI>27 kg/m2) will be recruited from the outpatient department of the Erasmus Medical Centre.After obtaining ≥5% of weight loss with a VLCD, participants will be randomly assigned to CPI or usual care for 10 weeks. CPI consists of cognitive behaviour therapy, problem solving therapy and proactive coping.Primary outcome measure is weight change (kg).Other outcome measures are Body Mass Index (BMI = weight (kg)/length (m)2), waist circumference (cm), systolic blood pressure (mmHg), HbA1c (mmol/mol), lipid levels (LDL, HDL, TG (mmol/l) and chol/HDL-ratio), antidiabetic agents and doses, cardiovascular risk profile (UKPDS), lifestyle and quality of life (EuroQol EQ-5D). Psychosocial parameters are also studied, as secondary outcomes as well as determinants for weight loss.When successful, we want to conduct an analysis of the cost effectiveness of the intervention as compared to usual care. DISCUSSION: We expect that a CPI after a VLCD will be effective in maintaining weight loss and improving cardiovascular risk and glycaemic control, while being cost-effective and improving quality of life in patients with type 2 diabetes. CLINICAL TRIALS REGISTRATION: trialregister.nl NTR2264.

Carotid atherosclerosis progression in familial hypercholesterolemia patients: a pooled analysis of the ASAP, ENHANCE, RADIANCE 1, and CAPTIVATE studies.

BACKGROUND: Until recently, patients with heterozygous familial hypercholesterolemia (HeFH) were considered the best subjects for the assessment of changes in carotid intima-media thickness (cIMT) in randomized intervention trials. Our aims were to investigate whether contemporary statin-treated HeFH patients still show accelerated cIMT increase and to assess the impact of statin treatment, before and after random assignment, on atherosclerosis progression. METHODS AND RESULTS: We retrospectively evaluated cIMT change, and prior statin treatment and postbaseline LDL-C change as predictors of cIMT change, in 1513 HeFH patients who were randomly assigned to the statin arms of the early ASAP and more recent RADIANCE 1, CAPTIVATE, and ENHANCE studies. In the 3 recent studies combined, mean cIMT increased at only 33%of the rate of the simvastatin-treated patients in the ASAP study (0.014 mm/2 years [95% confidence interval, -0.0003-0.028] versus 0.041 mm/2 years [95% confidence interval, 0.020-0.061]; P<0.05). Patients whose statin therapy could be intensified, as evidenced by an LDL-C decrease after the initiation of on-trial statin therapy, showed cIMT decrease in the first 6 to 12 months and a much lower cIMT increase measured over the full 2 years. In line with this, previously statin-naive HeFH patients showed a lower overall cIMT increase. CONCLUSIONS: Over the years, intensification of statin therapy in HeFH patients has resulted in an impressive decrease in carotid atherosclerosis progression. In studies that assess other antiatherosclerotic modalities, statin therapy may still induce rapid changes in cIMT. For future cIMT studies, our analyses suggest that patient populations other than intensively pretreated HeFH patients should be selected and that the statin regimen should not be changed on study initiation.

Mortality risk prediction by an insurance company and long-term follow-up of 62,000 men.

BACKGROUND: Insurance companies use medical information to classify the mortality risk of applicants. Adding genetic tests to this assessment is currently being debated. This debate would be more meaningful, if results of present-day risk prediction were known. Therefore, we compared the predicted with the observed mortality of men who applied for life insurance, and determined the prognostic value of the risk assessment. METHODS: Long-term follow-up was available for 62,334 male applicants whose mortality risk was predicted with medical evaluation and they were assigned to five groups with increasing risk from 1 to 5. We calculated all cause standardized mortality ratios relative to the Dutch population and compared groups with Cox's regression. We compared the discriminative ability of risk assessments as indicated by a concordance index (c). RESULTS: In 844,815 person years we observed 3,433 deaths. The standardized mortality relative to the Dutch male population was 0.76 (95 percent confidence interval, 0.73 to 0.78). The standardized mortality ratios ranged from 0.54 in risk group 1 to 2.37 in group 5. A large number of risk factors and diseases were significantly associated with increased mortality. The algorithm of prediction was significantly, but only slightly better than summation of the number of disorders and risk factors (c-index, 0.64 versus 0.60, P<0.001). CONCLUSIONS: Men applying for insurance clearly had better survival relative to the general population. Readily available medical evaluation enabled accurate prediction of the mortality risk of large groups, but the deceased men could not have been identified with the applied prediction method.

Molecular screening for familial hypercholesterolaemia: consequences for life and disability insurance.

In The Netherlands, cascade screening to identify patients with familial hypercholesterolaemia (FH) has been introduced in 1994; a nationwide screening programme is currently ongoing to detect all - approximately 40 000 - carriers by molecular screening. Active identification by DNA testing has social implications such as difficulties in obtaining life and disability insurance. In The Netherlands, insurance companies are restricted in the use of genetic information of their clients by the Medical Examination Act (1998). Within the scope of this specific law, the Foundation for the Identification of Persons with Inherited Hypercholesterolaemia, the patient support association, representatives of the medical profession as well as insurers designed guidelines for risk assessment of mortality and morbidity of FH carriers. Risk assessment should be based on phenotype, that is, lipoprotein profile and the presence of classical cardiovascular risk, instead of the LDL receptor gene mutation. Applicants with FH should be accepted at normal rates if LDL-c levels are <4.0 mmol/l, in the absence of additional risk factors. After implementation of these guidelines, the number of complaints about insurance contracts has decreased markedly.

Familial defective apolipoprotein B versus familial hypercholesterolemia: an assessment of risk.

Patients with familial hypercholesterolemia (FH) or familial defective apolipoprotein B (FDB) have severely increased low-density lipoprotein (LDL)-cholesterol levels and increased risk for premature coronary artery disease (CAD). Previous data on FDB patients were collected in patients referred to lipid clinics and were therefore subject to referral bias. We assessed the clinical phenotype of FDB in a population free from selection on CAD to compare the atherosclerotic burden with that of heterozygous FH. The study population was actively recruited in a large-scale screening program for inherited hypercholesterolemia in which FH and FDB heterozygotes were diagnosed by standard molecular techniques. Patients with FH and FDB had significantly higher plasma total cholesterol and LDL-cholesterol levels compared with their unaffected relatives. As with previous findings in FH, in FDB 19% of the carriers and 17% of the noncarriers of apoB mutations would have been misdiagnosed by cholesterol measurement alone, taking the age- and sex-specific 95th percentile as the diagnostic criterion. In FH patients the CAD risk was 8.5 relative to unaffected family members, whereas FDB patients had a 2.7-fold higher risk of CAD than unaffected relatives. FDB patients, free from clinical selection bias, do show lower total and LDL-cholesterol levels and lower CAD risk compared with FH heterozygotes. However, FDB patients are still exposed to a substantially higher CAD risk compared with unaffected relatives.