Clinical utility of expanded carrier screening: results-guided actionability and outcomes

PurposeExpanded carrier screening (ECS) informs couples of their risk of having offspring affected by certain genetic conditions. Limited data exists assessing the actions and reproductive outcomes of at-risk couples (ARCs). We describe the impact of ECS on planned and actual pregnancy management in the largest sample of ARCs studied to date.MethodsCouples who elected ECS and were found to be at high risk of having a pregnancy affected by at least one of 176 genetic conditions were invited to complete a survey about their actions and pregnancy management.ResultsThree hundred ninety-one ARCs completed the survey. Among those screened before becoming pregnant, 77% planned or pursued actions to avoid having affected offspring. Among those screened during pregnancy, 37% elected prenatal diagnostic testing (PNDx) for that pregnancy. In subsequent pregnancies that occurred in both the preconception and prenatal screening groups, PNDx was pursued in 29%. The decision to decline PNDx was most frequently based on the fear of procedure-related miscarriage, as well as the belief that termination would not be pursued in the event of a positive diagnosis.ConclusionECS results impacted couples' reproductive decision-making and led to altered pregnancy management that effectively eliminates the risk of having affected offspring.     

Knowledge and perceptions of haemoglobinopathy carrier screening among general practitioners in Cardiff.

A questionnaire was sent to 164 principal general practitioners working in Cardiff. A response rate of 81% was achieved. A total of 70% of respondents had had professional contact with a carrier for thalassaemia and a similar number for sickle cell disease, while 57% had recommended that a patient should be screened for haemoglobinopathy status. GPs tended to underestimate greatly the prevalence of haemoglobinopathies in South Glamorgan, and were uncertain of the ethnic minorities that were at particular risk. A carrier screening programme was considered justified by the majority of GPs in Cardiff and reasons for this opinion were examined. However, before a screening programme is started, information on whom to screen and their relative risk needs to be made more widely available.     

Attitudes of the general population towards preconception expanded carrier screening for autosomal recessive disorders including inborn errors of metabolism

Background

A substantial number of severely debilitating and often ultimately fatal inborn errors of metabolism (IEMs) still lack an effective disease-modifying treatment. Informing couples before a pregnancy about an increased risk of having a child with an inherited disorder is now feasible by preconception expanded carrier screening (ECS). While knowledge about carrier status enhances reproductive autonomy, it may also result in ethical dilemmas. The purpose of this study was to assess the attitudes of the general Dutch population towards preconception ECS and to investigate which factors influence these attitudes.

Developing intermediate care provided by general practitioners with a special interest: the economic perspective.

The concept of intermediate care is part of the National Health Service (NHS) modernization agenda to make services more flexible and accessible. One objective is for the general practitioner with a special interest (GPwSI) to provide a variety of extended services in a primary care setting that have been traditionally provided in secondary care. This development is underpinned by the hope that primary care organisations (PCOs) will provide more effective and efficient care in local settings, but, as with other skill-mix changes, the process has developed ahead of an evidence base of effectiveness or cost-effectiveness. This paper considers intermediate care from an economic perspective and provides healthcare commissioners with a background that can facilitate resource allocation decisions. It cautions that, unless the economic issues are carefully considered, there is a danger that services may be introduced that are thought to be efficient, when in fact they may not be so.     

The evolving landscape of expanded carrier screening: challenges and opportunities

PurposeCarrier screening allows individuals to learn their chance of passing on an autosomal or X-linked condition to their offspring. Initially introduced as single-disease, ancestry-based screening, technological advances now allow for the possibility of multi-disease, pan-ethnic carrier screening, which we refer to as “expanded carrier screening.” There are numerous potential benefits to expanded carrier screening, including maximizing the opportunity for couples to make autonomous reproductive decisions, and efficiency and marginal additional costs of including more conditions if the test is already being offered. While numerous laboratories currently offer expanded carrier screening services, it is not yet commonly used in clinical practice, and there is a lack of consensus among experts about the service, including whether this should be offered to individuals and couples, whether this should be offered preconception or prenatally, and what conditions to include in screening programs. Challenges for expanded carrier screening programs include a lack of demand from the public, low prioritization by health systems, the potential for pressure to undergo screening, the possibility of disability-based discrimination, needed adaptations to pre- and post-test counseling, technical limitations, and the evolving technological and socio-political landscape.     

Clinical experience with carrier screening in a general population: support for a comprehensive pan-ethnic approach

PurposeTo present results from a large cohort of individuals receiving expanded carrier screening (CS) in the United States.MethodsSingle-gene disorder carrier status for 381,014 individuals was determined using next-generation sequencing (NGS) based CS for up to 274 genes. Detection rates were compared with literature-reported values derived from disease prevalence and carrier frequencies. Combined theoretical affected pregnancy rates for the 274 screened disorders were calculated.ResultsFor Ashkenazi Jewish (AJ) diseases, 81.6% (4434/5435) of carriers identified did not report AJ ancestry. For cystic fibrosis, 44.0% (6260/14,229)of carriers identified had a variant not on the standard genotyping panel. Individuals at risk of being a silent spinal muscular atrophy carrier, not detectable by standard screening, comprised 1/39 (8763/344,407) individuals. For fragile X syndrome, compared with standard premutation screening, AGG interruption analysis modified risk in 83.2% (1128/1356) premutation carriers. Assuming random pairing across the study population, approximately 1/175 pregnancies would be affected by a disorder in the 274-gene screening panel.ConclusionCompared with standard screening, NGS-based CS provides additional information that may impact reproductive choices. Pan-ethnic CS leads to substantially increased identification of at-risk couples. These data support offering NGS-based CS to all reproductive-aged women.     

Access to general practice and general practitioners by telephone: the patient's view.

Postal surveys were conducted among samples of patients in four practices to determine accessibility of surgeries and general practitioners by telephone. Over half of the respondents reported being unable to get through to the surgery on their first attempt. Significant differences between practices were related to the number of patients served by each incoming line. Although all of the general practitioners involved were accessible to patients by telephone, only half of the respondents knew this. Significant differences in awareness levels between practices were related to policies and methods of disseminating this information. Satisfaction with the help received from doctors by telephone was uniformly high, but patients were less satisfied with the process of contacting a doctor, particularly where receptionists questioned callers about their problem. It is suggested that practices review the adequacy of their telephone systems against a recommended standard of one incoming line per 2500 patients and consider how information about their telephone policies and services can be effectively communicated to patients. Reception staff may need additional guidance on managing telephone contacts with patients.     

Evaluation of an educational programme to improve the recognition of psychological illness by general practitioners.

BACKGROUND: Take Care is a commercially sponsored educational package for the detection and management of depression by all members of the primary health-care team. AIM: This study was designed to evaluate whether the educational package affects the recognition of psychological illness by general practitioners. METHOD: General practitioners working in 13 practices in North West England or Trent Regional Health Authorities took part the evaluation. Patients who scored more than eight on the depression or anxiety component of the Hospital Anxiety and Depression (HAD) scales, and who were thought by their general practitioner to have a totally physical problem or no illness, were deemed to have a psychological illness that had been 'missed' by the doctor. Changes in the proportion of missed cases before and after exposure to Take Care were estimated. RESULTS: When all practices were considered together, the general practitioners missed a depressive illness in 24.1% of patients before Take Care, and 17.1% afterwards; absolute decrease 7.0% [95% confidence interval (CI) -2.0 to -12.0%]. An improvement was seen in most practices (Wilcoxon matched-pair test P < 0.05). The programme was also associated with a small reduction in the overall proportion of episodes of anxiety missed by the doctor (absolute decrease 4.5%; 95% CI -1.0 to -8.0%) a reduction was found in most practices (Wilcoxon matched-pair test P < 0.05). There was no material difference in the diagnostic false-positive rate of the doctors before and after the introduction of the programme. CONCLUSION: Exposure to an educational package for depression was associated with improved recognition of psychological illness by general practitioners.     

Systematic review of outcomes in studies of reproductive genetic carrier screening: Towards development of a core outcome set

PurposeCurrent practice recommendations support the widespread implementation of reproductive genetic carrier screening (RGCS). These consensus-based recommendations highlight a research gap, with findings from current studies being insufficient to meet the standard required for more rigorous evidence-based recommendations. This systematic review assessed methodological aspects of studies on RGCS to inform the need for a core outcome set.MethodsWe conducted a systematic search to identify peer-reviewed published studies offering population-based RGCS. Study designs, outcomes, and measurement methods were extracted. A narrative synthesis was conducting using an existing outcome taxonomy and criteria used in the evaluation of genetic screening programs as frameworks.ResultsSixty-five publications were included. We extracted 120 outcomes representing 24 outcome domains. Heterogeneity in outcome selection, measurement methods and time points of assessment was extensive. Quality appraisal raised concerns for bias. We found that reported outcomes had limited applicability to criteria used to evaluate genetic screening programs.ConclusionDespite a large body of literature, diverse approaches to research have limited the conclusions that can be cumulatively drawn from this body of evidence. Consensus regarding meaningful outcomes for evaluation of RGCS would be a valuable first step in working towards evidence-based practice recommendations, supporting the development of a core outcome set.     

Care provided by the general practitioner to cancer patients

This article describes the development of a checklist that defines points of attention for the general practitioner in cases of cancer. The points of attention concern the care, in the widest sense of the word, provided to cancer patients. Emphasis is placed upon the care in situations in which the cancer patient is confronted with many problems and uncertainties. The literature was first examined for definitions of ‘elements of adequate care’. These were next submitted for critical assessment and supplementation to a panel of patients, persons in their immediate environment, general practitioners and other care providers. Both the procedure followed (a variant of the Delphi method) and the principal findings are discussed. Some attention will be paid to the question of the validity of the panel results, by indicating how far a random sample of general practitioners did share the views of the panel. In addition, it will briefly be discussed how another random sample of general practitioners actually performs - in their own opinion - with respect to several points of attention.     

Informed decision making and psychosocial outcomes in pregnant and nonpregnant women offered population fragile X carrier screening

PurposePopulation-based carrier screening for fragile X syndrome (FXS) is still not universally endorsed by professional organizations due to concerns around genetic counseling for complex information and potential for psychosocial harms.MethodsWe determined uptake levels, decision making, and psychosocial impact in a prospective study of pregnant and nonpregnant Australian women offered FXS carrier screening in clinical settings. Women received pretest genetic counseling, and completed questionnaires when deciding and one month later.ResultsOf 1,156 women recruited, 83.1% returned the first questionnaire with 70.6% nonpregnant and 58.8% pregnant women choosing testing (χ²=16.98,P<0.001). Overall, informed choice was high in both nonpregnant (77.4%) and pregnant (72.9%) women (χ²=0.21,P=0.644), and more tested (76.0%) than not-tested (66.7%) women (χ²=6.35,P=0.012) made an informed choice. Measures of depression, stress, and anxiety were similar to population norms for ~85% of women. Decisional conflict and regret were generally low; however, decisional uncertainty and regret were greater in pregnant than nonpregnant women, and not-tested than tested women (uncertainty: χ²=18.51,P<0.001 and χ²=43.11,P<0.001, respectively; regret: χ²=6.61,P<0.037 and χ²=35.54,P<0.001, respectively).ConclusionWe provide evidence to inform guidelines that population FXS carrier screening can be implemented with minimal psychosocial harms following appropriate information and prescreening genetic counseling.     

Glutaric acidemia type 1: outcomes before and after expanded newborn screening

Glutaric acidemia type 1 (GA-1) is an autosomal recessive disorder of lysine, hydroxylysine, and tryptophan metabolism. Patients may present with brain atrophy, macrocephaly, and acute dystonia secondary to striatal degeneration typically triggered by an infection, fever, and/or dehydration. This disorder is identified on expanded newborn screening by increased glutarylcarnitine. We evaluated the outcome of 19 patients with GA-1. Ten patients were diagnosed by newborn screening and 9 were diagnosed clinically. DNA testing in 12 patients identified 15 different mutations in the glutaryl-CoA dehydrogenase gene. Plasma glutarylcarnitine and urinary 3-hydroxyglutaric acid were elevated in all patients. However, only 10 of 17 patients who underwent urine organic acid analysis were high excretors of glutaric acid. Levels of glutarylcarnitine in plasma correlated with the urinary excretion of glutaric and 3-hydroxyglutaric acid, but not with clinical outcome. Plasma lysine was also significantly correlated with urinary glutaric acid, but not with urinary 3-hydroxyglutaric acid. Brain magnetic resonance imaging in all patients showed wide Sylvian fissures before treatment, which normalized by 4 years of age in treated patients. The occurrence of three adverse outcomes (oral motor function, ambulatory capability, and dystonic movements) was on average reduced by 75% (relative risk 0.25 to 0.28) in patients identified by newborn screening compared to patients diagnosed before newborn screening (Fisher's exact test; p=0.0055 for oral motor function and ambulatory capability; p=0.023 for dystonic movements). Newborn screening is effective in the prevention of complications in patients with GA-1 when coupled with treatment strategies.     

Colorectal cancer risk perceptions and screening intentions in a minority population

This is a 2-year follow-up to a previously reported baseline paper. We focused on a predominantly low-income African-American population from a community health center and investigated the relationships among perceptions of perceived risks for colorectal cancer (CRC), concerns about getting CRC, screening intentions, and whether participants had a fecal occult blood test (FOBT) on schedule at follow-up. Baseline absolute risk did not predict screening intentions or being on schedule (15% of sample), nor did it predict follow-up perceived absolute risk, comparative risk, or CRC concerns. Participants who expressed greater perceived absolute risk, comparative risk, and concerns at follow-up were more likely to report thinking about or definitely planning to get an FOBT within the next 2 years (49% of the sample). In addition, baseline absolute risk and whether or not a person had an FOBT on schedule at baseline did not predict being on schedule at follow-up. A significant percentage of the population (20%) were not able to state whether their CRC risk was below average, average, or above average. In addition, 44% of the population viewed their risks as lower than their peers, and 58% reported being not at all or slightly concerned about getting CRC. These results suggest that educational efforts are needed especially for low-income minority populations to enhance knowledge and accuracy of risk perceptions for CRC and interventions that explicitly manipulate risk are needed to assess to what extent risk perceptions can be modified and subsequently affect screening.     

Provision of smoking cessation counseling by general practitioners assisted by training and screening procedure

OBJECTIVE: To examine which counseling behavior among GPs can be achieved after counseling training when organizational support is provided. METHODS: A random sample of 39 general practices was drawn, 34 took part. GPs received a pre-study assessment followed by a training session for smoking counseling. All patients showing up during a period of 1 week were asked about smoking status. Current smokers, aged 18-70 years were eligible (N=551), 81.8% participated. A documentation sheet, filled in by a study nurse transferred smoking-related information about patient to the GP. GPs were advised to fill in a post-counseling assessment for every patient. A post-study assessment with the GPs was conducted. RESULTS: Frequent barriers for smoking counseling were lack of time and the assumption that patients were not motivated to quit. The GP's documented smoking counseling in 96.0%. The patients (87.8%) could be thoroughly counseled. Younger age of the GP, a high number of patients and the contemplation stage quitting smoking were predictors for realizing counseling. 79.3% of the GPs assessed the procedure to be practicable. CONCLUSIONS: Smoking counseling in the general practice is feasible. PRACTICE IMPLICATION: Involving staff in the screening procedure may support counseling activity of the GP.     

A data-driven evaluation of the size and content of expanded carrier screening panels

PurposeThe American College of Obstetricians and Gynecologists (ACOG) proposed seven criteria for expanded carrier screening (ECS) panel design. To ensure that screening for a condition is sufficiently sensitive to identify carriers and reduce residual risk of noncarriers, one criterion requires a per-condition carrier rate greater than 1 in 100. However, it is unestablished whether this threshold corresponds with a loss in clinical detection. The impact of the proposed panel design criteria on at-risk couple detection warrants data-driven evaluation.MethodsCarrier rates and at-risk couple rates were calculated in 56,281 patients who underwent a 176-condition ECS and were evaluated for panels satisfying various criteria. Condition-specific clinical detection rates were estimated via simulation.ResultsDifferent interpretations of the 1-in-100 criterion have variable impact: a compliant panel would include between 3 and 38 conditions, identify11–81% fewer at-risk couples, and detect 36–79% fewer carriers than a176-condition panel. If the carrier rate threshold must be exceeded in all ethnicities, ECS panels would lack prevalent conditions like cystic fibrosis. Simulations suggest that the clinical detection rate remains >84% for conditions with carrier rates as low as 1 in 1000.ConclusionThe 1-in-100 criterion limits at-risk couple detection and should be reconsidered.