Air pollution accountability research: Moving from a chain to a web.

Air pollution accountability studies examine the relationship(s) between an intervention, regulation, or event and the resulting downstream impacts, if any, on emissions, exposure, and/or health. The sequence of events has been schematically described as an accountability chain. Here, we update the existing framework to capture real-life complexities and to highlight important factors that fall outside the linear chain. This new "accountability web" is intended to convey the intricacies associated with conducting an accountability study to various audiences, including researchers, policy makers, and stakeholders. We also identify data considerations for planning and completing a robust accountability study, including those relevant to novel and innovative air pollution and exposure data. Finally, we present a series of recommendations for the accountability research community that can serve as a guide for the next generation of accountability studies.

Should germline genome editing be allowed? The effect of treatment characteristics on public acceptability.

STUDY QUESTION: To what extent do characteristics of germline genome editing (GGE) determine whether the general public supports permitting the clinical use of GGE? SUMMARY ANSWER: The risk that GGE would cause congenital abnormalities had the largest effect on support for allowing GGE, followed by effectiveness of GGE, while costs, the type of application (disease or enhancement) and the effect on child well-being had moderate effects. WHAT IS KNOWN ALREADY: Scientific progress on GGE has increased the urgency of resolving whether and when clinical application of GGE may be ethically acceptable. Various expert bodies have suggested that the treatment characteristics will be key in determining whether GGE is acceptable. For example, GGE with substantial risks (e.g. 15% chance of a major congenital abnormality) may be acceptable to prevent a severe disease but not to enhance non-medical characteristics or traits of an otherwise healthy embryo (e.g. eye colour or perhaps in the future more complex traits, such as intelligence). While experts have called for public engagement, it is unclear whether and how much the public acceptability of GGE is affected by the treatment characteristics proposed by experts. STUDY DESIGN, SIZE, DURATION: The vignette-based survey was disseminated in 2018 among 1857 members of the Dutch general public. An online research panel was used to recruit a sample representing the adult Dutch general public. PARTICIPANTS/MATERIALS, SETTING, METHODS: A literature review identified the key treatment characteristics of GGE: the effect on the well-being of the future child, use for disease or enhancement, risks for the future child, effectiveness (here defined as the chance of a live birth, assuming that if the GGE was not successful, the embryo would not be transferred), cost and availability of alternative treatments/procedures to prevent the genetic disease or provide enhancement (i.e. preimplantation genetic testing (PGT)), respectively. For each treatment characteristic, 2-3 levels were defined to realistically represent GGE and its current alternatives, donor gametes and ICSI with PGT. Twelve vignettes were created by fractional factorial design. A multinominal logit model assessed how much each treatment characteristic affected participants' choices. MAIN RESULTS AND THE ROLE OF CHANCE: The 1136 respondents (response rate 61%) were representative of the Dutch adult population in several demographics. Respondents were between 18 and 89 years of age. When no alternative treatment/procedure is available, the risk that GGE would cause (other) congenital abnormalities had the largest effect on whether the Dutch public supported allowing GGE (coefficient = -3.07), followed by effectiveness (coefficient = 2.03). Costs (covered by national insurance, coefficient = -1.14), the type of application (disease or enhancement; coefficient = -1.07), and the effect on child well-being (coefficient = 0.97) had similar effects on whether GGE should be allowed. If an alternative treatment/procedure (e.g. PGT) was available, participants were not categorically opposed to GGE, however, they were strongly opposed to using GGE for enhancement (coefficient = -3.37). The general acceptability of GGE was higher than participants' willingness to personally use it (P < 0.001). When participants considered whether they would personally use GGE, the type of application (disease or enhancement) was more important, whereas effectiveness and costs (covered by national insurance) were less important than when they considered whether GGE should be allowed. Participants who were male, younger and had lower incomes were more likely to allow GGE when no alternative treatment/procedure is available. LIMITATIONS, REASONS FOR CAUTION: Some (e.g. ethnic, religious) minorities were not well represented. To limit complexity, not all characteristics of GGE could be included (e.g. out-of-pocket costs), therefore, the views gathered from the vignettes reflect only the choices presented to the respondents. The non-included characteristics could be connected to and alter the importance of the studied characteristics. This would affect how closely the reported coefficients reflect 'real-life' importance. WIDER IMPLICATIONS OF THE FINDINGS: This study is the first to quantify the substantial impact of GGE's effectiveness, costs (covered by national insurance), and effect on child well-being on whether the public considered GGE acceptable. In general, the participants were strikingly risk-averse, in that they weighed the risks of GGE more heavily than its benefits. Furthermore, although only a single study in one country, the results suggests that-if sufficiently safe and effective-the public may approve of using GGE (presumably combined with PGT) instead of solely PGT to prevent passing on a disease. The reported public views can serve as input for future consideration of the ethics and governance of GGE. STUDY FUNDING/COMPETING INTEREST(S): Young Academy of the Royal Dutch Academy of Sciences (UPS/RB/745), Alliance Grant of the Amsterdam Reproduction and Development Research Institute (2017-170116) and National Institutes of Health Intramural Research Programme. No competing interests. TRIAL REGISTRATION NUMBER: N/A.

Psychological factors associated with the intention to choose for risk-reducing mastectomy in family cancer clinic attendees.

OBJECTIVES: Women seeking counseling because of familial breast cancer occurrence face difficult decisions, such as whether and when to opt for risk-reducing mastectomy (RRM) in case of BRCA1/2 mutation. Only limited research has been done to identify the psychological factors associated with the decision for RRM. This study investigated which psychological factors are related to the intention to choose for RRM. MATERIALS & METHODS: A cohort of 486 cancer-unaffected women with a family history of breast cancer completed the following questionnaires prior to genetic counseling: the Cancer Worry Scale, Positive And Negative Affect Scale, Perceived Personal Control Scale, Hospital Anxiety and Depression Scale and State Anxiety Scale and questions regarding socio-demographic characteristics, family history, risk perception and RRM intention. Multivariate logistic regression was used to analyze the relation between psychological factors and women's intention to choose for RRM. RESULTS: Factors associated with RRM intention were high positive affect (OR = 1.86, 95%CI = 1.12-3.08), high negative affect (OR = 2.52, 95%CI = 1.44-4.43), high cancer worry (OR = 1.65, 95%CI = 1.00-2.72), high perceived personal control (OR = 3.58, 95%CI = 2.18-5.89), high risk-perception (OR = 1.85, 95%CI = 1.15-2.95) and having children (OR = 2.06, 95%CI = 1.21-3.50). CONCLUSION: Negative and positive affects play an important role in the intention for RRM. Furthermore, perceived personal control over the situation is associated with an intention for RRM. In addition to focusing on accurate risk communication, counseling should pay attention to the influence of perceived control and emotions to facilitate decision-making.

Determining the genome-wide kinship coefficient seems unhelpful in distinguishing consanguineous couples with a high versus low risk for adverse reproductive outcome.

BACKGROUND: Offspring of consanguineous couples are at increased risk of congenital disorders. The risk increases as parents are more closely related. Individuals that have the same degree of relatedness according to their pedigree, show variable genomic kinship coefficients. To investigate whether we can differentiate between couples with high- and low risk for offspring with congenital disorders, we have compared the genomic kinship coefficient of consanguineous parents with a child affected with an autosomal recessive disorder with that of consanguineous parents with only healthy children, corrected for the degree of pedigree relatedness. METHODS: 151 consanguineous couples (73 cases and 78 controls) from 10 different ethnic backgrounds were genotyped on the Affymetrix platform and passed quality control checks. After pruning SNPs in linkage disequilibrium, 57,358 SNPs remained. Kinship coefficients were calculated using three different toolsets: PLINK, King and IBDelphi, yielding five different estimates (IBDelphi, PLINK (all), PLINK (by population), King robust (all) and King homo (by population)). We performed a one-sided Mann Whitney test to investigate whether the median relative difference regarding observed and expected kinship coefficients is bigger for cases than for controls. Furthermore, we fitted a mixed effects linear model to correct for a possible population effect. RESULTS: Although the estimated degrees of genomic relatedness with the different toolsets show substantial variability, correlation measures between the different estimators demonstrated moderate to strong correlations. Controls have higher point estimates for genomic kinship coefficients. The one-sided Mann Whitney test did not show any evidence for a higher median relative difference for cases compared to controls. Neither did the regression analysis exhibit a positive association between case-control status and genomic kinship coefficient. CONCLUSIONS: In this case-control setting, in which we compared consanguineous couples corrected for degree of pedigree relatedness, a higher degree of genomic relatedness was not significantly associated with a higher likelihood of having an affected child. Further translational research should focus on which parts of the genome and which pathogenic mutations couples are sharing. Looking at relatedness coefficients by determining genome-wide SNPs does not seem to be an effective measure for prospective risk assessment in consanguineous parents.

A genetic diagnosis of maturity-onset diabetes of the young (MODY): experiences of patients and family members.

AIMS: Genetic testing for maturity-onset diabetes of the young (MODY) facilitates a correct diagnosis, enabling treatment optimization and allowing monitoring of asymptomatic family members. To date, the majority of people with MODY remain undiagnosed. To identify patients' needs and areas for improving care, this study explores the experiences of patients and family members who have been genetically tested for MODY. METHODS: Fourteen semi-structured interviews with patients and the parents of patients, and symptomatic and asymptomatic family members were conducted. Atlas.ti was used for thematic analysis. RESULTS: Most people with MODY were initially misdiagnosed with Type 1 or Type 2 diabetes; they had been seeking for the correct diagnosis for a long time. Reasons for having a genetic test included reassurance, removing the uncertainty of developing diabetes (in asymptomatic family members) and informing relatives. Reasons against testing were the fear of genetic discrimination and not having symptoms. Often a positive genetic test result did not come as a surprise. Both patients and family members were satisfied with the decision to get tested because it enabled them to adjust their lifestyle and treatment accordingly. All participants experienced a lack of knowledge of MODY among healthcare professionals, in their social environment and in patient organizations. Additionally, problems with the reimbursement of medical expenses were reported. CONCLUSIONS: Patients and family members are generally positive about genetic testing for MODY. More education of healthcare professionals and attention on the part of diabetes organizations is needed to increase awareness and optimize care and support for people with MODY.

Informed consent for exome sequencing in diagnostics: exploring first experiences and views of professionals and patients.

Next-generation sequencing is increasingly being chosen as a diagnostic tool for cases of expected genetic, but unresolved origin. The consequential increased need for decisions on disclosure of unsolicited findings poses a challenge for the informed consent procedure. This study explored the first experiences with, and needs for, the informed consent procedure in diagnostic exome sequencing, with the stakeholders involved. Semi-structured interviews were conducted with 11 professional experts and one professional gave a written response. Furthermore, the counseling process was observed in three cases where exome sequencing was offered, followed by interviews with the patient (representative) and the genetic counselor. The respondents not only preferred an opt-out for unsolicited findings but also identified many challenges and therefore more experiences with exome sequencing was considered needed. Context-dependent decision-making was observed and an Advisory Board for unsolicited findings was considered helpful while doubts were raised about the feasibility and the possibility of undermining patients' autonomy. Finally, respondents brought up the complexity of information provision, and division of responsibilities between clinicians and the lab. These challenges and needs, raised by stakeholders involved, provide more insight in the next steps needed for an optimal informed consent procedure for exome sequencing in diagnostics.

'A morass of considerations': exploring attitudes towards ethnicity-based haemoglobinopathy-carrier screening in primary care.

BACKGROUND: The Netherlands does not have a national haemoglobinopathy (HbP)-carrier screening programme aimed at facilitating informed reproductive choice. HbP-carrier testing for those at risk is at best offered on the basis of anaemia. Registration of ethnicity has proved controversial and may complicate the introduction of a screening programme if based on ethnicity. However, other factors may also play a role. OBJECTIVE: To explore perceived barriers and attitudes among GPs and midwives regarding the registration of ethnicity and ethnicity-based HbP-carrier screening. METHODS: Six focus groups in Dutch primary care, with a total of 37 GPs (n = 9) and midwives (n = 28) were conducted, transcribed and content analysed using Atlas-ti. RESULTS: Both GPs and midwives struggled with correctly identifying ethnicities at risk for HbP. Ethical concerns regarding privacy seemed to originate from World War II experiences, when ethnic and religious registration facilitated deportation of Jewish citizens, coupled with the political climate at the time focus groups were held. Some respondents thought the ethnicity question might undermine the relationship with their clients. Software programmes prevented GPs from registering ethnicity of patients at risk. Financial implications for patients were also a concern. Despite this, respondents seemed positive about screening and were familiar with identifying ethnicity and used this for individual patient care. CONCLUSIONS: Although health professionals are generally positive about screening, ethical, financial and practical issues surrounding ethnicity-based HbP-carrier screening need to be clarified before introducing such a programme. Primary care professionals can be targeted through professional organizations but they need national policy support.

Being at risk for cardiovascular disease: perceptions and preventive behavior in people with and without a known genetic predisposition.

This study compares and explains differences in perceptions of cardiovascular disease (CVD) risk and preventive behaviors in people with and without a known genetic predisposition to CVD. A cross-sectional study using two samples was performed. The first sample (genetic predisposition; n = 51) consisted of individuals recently diagnosed with familial hypercholesterolemia (FH) through DNA testing. The second sample (no genetic predisposition; n = 49) was recruited among patients with CVD-risk profiles based on family history of CVD, cholesterol levels, and blood pressure, registered at general practices. Participants filled out a postal questionnaire asking about their perceived risk, causal attributions (i.e. genetic and lifestyle), and about perceived efficacy and adoption of preventive behavior (i.e. medication adherence and adoption of a healthy diet and being sufficiently active). Perceived comparative risk, genetic attributions of CVD, and perceived efficacy of medication were higher in the "genetic predisposition" sample than in the "no genetic predisposition" sample. The samples did not differ on lifestyle attributions, efficacy of a healthy lifestyle, or preventive behavior. Individual differences in perceived risk, genetic attributions, perceived efficacy of medication, and adoption of a healthy lifestyle were best explained by family history of CVD. Our findings suggest that in people diagnosed with a single gene disorder characterized by a family disease history such as FH, family disease history may be more important than DNA information in explaining perceptions of and responses to risk.

Reproductive behavior of individuals with increased risk of having a child with retinoblastoma.

To investigate reproductive behavior of individuals at increased risk of having a child with retinoblastoma (Rb), we conducted a cross-sectional questionnaire survey among 118 counselees visiting the Clinical Genetics Department of the National Rb Center in the Netherlands. The recurrence risk for counselees ranged from <1% to 50%. The response rate was 69%. Of 43 respondents considering having children after becoming aware of their increased risk, Rb influenced reproductive behavior for 25 (58%), of whom 14 had a recurrence risk <3%. Twenty of these 25 decided against having more children and 5 used prenatal diagnosis. Eighteen of the 43 respondents did not use any of the alternative reproductive options and had children (or more children), although half indicated having had doubts about their decisions. Multiple logistic regression showed that only perceived risk (p = 0.003) was significantly associated with Rb influencing reproductive behavior. Of 17 respondents planning children (or more children), 11 (65%) considered using one of the alternative reproductive options. We conclude that reproductive behavior is greatly influenced by Rb and that perceived risk, not objective risk, is the most important factor of influence. It is important to offer individuals at increased risk continued access to genetic counseling, even when this risk is small.

'A low risk is still a risk': exploring women's attitudes towards genetic testing for breast cancer susceptibility in order to target disease prevention.

BACKGROUND: Population breast cancer screening programs by mammography are offered to women based on age. It has been suggested that a screening program based on genetic risk profile could be more effective by targeting interventions at those at higher genetic risk. This study explores women's attitudes towards genetic testing for breast cancer susceptibility in order to target breast cancer prevention. METHODS: A qualitative study was conducted using 4 focus groups with 26 women aged 42-73 years. Women were selected irrespective of personal or family history of breast cancer. Discussions were audiotaped and content analyzed. RESULTS: The results show that in general women are positive towards a breast cancer screening program based on genetic risk profile, provided that in the low-risk group, though less frequent, women are still offered mammography screening (i.e. right to screening (a)). Other themes that women addressed were: (b) value of the genetic risk information (e.g. possibilities for cancer prevention at younger ages, less screening burden for low-risk women), (c) personal autonomy (e.g. free choice to undergo testing), (d) dealing with test results (e.g. burden of risk, motivation to reduce the risk), (e) discrimination, and (f) financial aspects and priority (e.g. with respect to other health care programs). CONCLUSION: These results suggest that women currently offered breast cancer screening based on age have a positive attitude towards population susceptibility screening for breast cancer, but also identified issues that need to be discussed and studied further, especially if women in the low-risk group were no longer to be offered mammography screening.

Compromized geranylgeranylation of RhoA and Rac1 in mevalonate kinase deficiency.

Mevalonate kinase deficiency (MKD) is an autoinflammatory disorder caused by mutations in the MVK gene resulting in decreased activity of the enzyme mevalonate kinase (MK). Although MK is required for biosynthesis of all isoprenoids, in MKD, in particular, the timely synthesis of geranylgeranyl pyrophosphate appears to be compromised. Because small guanosine triphosphatases (GTPases) depend on geranylgeranylation for their proper signaling function, we studied the effect of MK deficiency on geranylgeranylation and activation of the two small GTPases, RhoA and Rac1. We demonstrate that both geranylgeranylation and activation of the two GTPases are more easily disturbed in MKD cells than in control cells when the flux though the isoprenoid biosynthesis pathway is suppressed by low concentrations of simvastatin. The limited capacity of geranylgeranylation in MKD cells readily leads to markedly increased levels of nonisoprenylated and activated GTPases, which will affect proper signaling by these GTPases.

Reproductive decision-making: a qualitative study among couples at increased risk of having a child with retinoblastoma.

Little is known about the reproductive decision-making process of couples with an increased risk of having a child with retinoblastoma (Rb). A qualitative study was conducted to explore the impact of prospective risk on reproductive decisions, factors influencing these decisions, and the needs of couples with regard to reproductive counselling. Fourteen couples of childbearing age who received genetic counselling between 2002 and 2006 participated in semi-structured interviews in 2008. The risk of having a child with Rb ranged from less than 1% to 50%. In most cases, the diagnosis of Rb influenced subsequent family planning. Prenatal diagnosis was used by two couples, while others refrained from having more children. Reproductive decisions were influenced by the burden of the disease for the patient and family members, the impact of ophthalmological screening under anaesthesia, and couples' perceived risk, which did not always relate to their actual risk. Reproductive choices with regard to the number of children wanted changed over time. Our findings indicate topics to be discussed during genetic counselling of couples at increased risk for a child with Rb. We suggest continued access to genetic counselling also after the initial diagnosis and treatment.

[Television watching and some eating habits of 6-14-year-old children in Amsterdam, the Netherlands; a cross-sectional study]. / Televisiekijken en enkele eetgewoonten bij Amsterdamse 6-14-jarigen; een transversaal onderzoek.

OBJECTIVE: To describe the time spent by children between the ages of 6-14 years watching television during a weekday and to examine associated factors. DESIGN: Cross-sectional questionnaire study. METHOD: Data were collected during a vaccination campaign against meningococci C in Amsterdam in September 2002. From a sample of 2910 parents of 6-14-year-old children 1775 agreed to participate in the study. Socio-demographic characteristics and data on television viewing the previous day, the presence of a television in the child's bedroom and on eating habits were collected by short interviews. RESULTS: In total 1587 children were included in the analyses, 805 boys and 782 girls. In total 40.1% of the boys and 36.5% of the girls had watched television for > or = 2 h during the previous day. Among the children < or = 10 years 28.7% had a television in their bedroom, among children > 10 years this was 45.7%. Age (> 10 years), ethnicity (notably Surinam origin) and having a television in the bedroom was related to spending more time watching television. Having parents with a high socioeconomic status (SES) was associated with less television viewing than having parents with a lower SES. Children who had not eaten fresh fruit or who had visited a snackbar the previous day had been watching television for > or = 2 h more often than children who had eaten fresh fruit (p < 0.001) or who had not visited a snackbar (p < 0.05). CONCLUSION: Children spent a lot of time watching television. In view of the relation between television viewing and overweight this is an alarming development. Possibilities for the prevention of overweight by reducing television viewing must be investigated.

Possibilities and barriers in the implementation of a preconceptional screening programme for cystic fibrosis carriers: a focus group study.

OBJECTIVE: This qualitative study aimed to explore possibilities and barriers in the implementation of a nationwide preconceptional cystic fibrosis (CF) carrier screening programme. METHODS: Sessions were held with two focus groups of CF patients and CF relatives, one focus group of people from the target population (couples planning a pregnancy), and two focus groups of potential providers (general practitioners (GPs) and municipal health service workers). RESULTS: Important barriers in the implementation of a preconceptional CF carrier screening programme included the problem of reaching the target population, the heavy workload of GPs, the limited public knowledge about CF in general, and the absence of a preconceptional consultation setting. In general, there was a positive attitude among the participants towards CF carrier screening. CONCLUSION: This study revealed some important barriers in the implementation of CF carrier screening programmes. More research is needed to specify and quantify the importance of the various barriers. Eventually, different intervention strategies should be included in an implementation plan to overcome the most important barriers in the organization and execution of screening.

Preconception cystic fibrosis carrier couple screening: impact, understanding, and satisfaction.

The impact, understanding of test-results, and satisfaction among participating couples in a preconception cystic fibrosis (CF) carrier screening project were assessed 6 months after testing. Questionnaire data were obtained from 17/18 identified carriers, 15 partners of carriers with negative test results, and 794 (73%) other participants. None of the carriers changed their reproductive plans because of their test results. Eight participants were worried about their results, including four carriers. Those who attended a general practitioner (GP) consultation for pretest education were less worried than those who attended an educational session. Seven carriers felt less healthy. Predictors of a correct understanding of test results (correct in 62% of participants) were: positive test results, high level of knowledge of CF, high level of education, attending an educational session, and previously heard of CF. All participants who reported that they were worried, all carriers, and 95% of the other participants said that they would make the same decision to be tested again. Although couples who were educated during a GP consultation were less worried, the results of the study suggest that understanding is more correct in couples attending an educational session. The results further suggest that since satisfaction with the screening was high, worries and feeling less healthy due to the test results are probably not a great burden.