Barriers and facilitators for cascade testing in genetic conditions: a systematic review

Abstract

Cascade testing is the process of offering genetic counseling and testing to at-risk relatives of an individual who has been diagnosed with a genetic condition. It is critical for increasing the identification rates of individuals with these conditions and the uptake of appropriate preventive health services. The process of cascade testing is highly varied in clinical practice, and a comprehensive understanding of factors that hinder or enhance its implementation is necessary to improve this process. We conducted a systematic review to identify barriers and facilitators for cascade testing and searched PubMed, CINAHL via EBSCO, Web of Science, EMBASE, and the Cochrane Library for articles published from the databases’ inception to November 2018. Thirty articles met inclusion criteria. Barriers and facilitators identified from these studies at the individual-level were organized into the following categories: (1) demographics, (2) knowledge, (3) attitudes, beliefs, and emotional responses of the individual, and (4) perceptions of relatives, relatives’ responses, and attitudes toward relatives. At the interpersonal-level, barriers and facilitators were categorized as (1) family communication-, support- and dynamics-, and (2) provider-factors. Finally, barriers at the environmental-level relating to accessibility of genetic services were also identified. Our findings suggest that several individual, interpersonal and environmental factors may play a role in cascade testing. Future studies to further investigate these barriers and facilitators are needed to inform future interventions for improving the implementation of cascade testing for genetic conditions in clinical practice.

Introduction

Cascade testing is the process of offering genetic testing to at-risk relatives of an individual who has been diagnosed with a genetic condition (i.e., the index patient or proband). This process is critical for timely initiation of risk-management strategies such as surveillance and prophylactic strategies, and is widely used in autosomal dominant conditions such as familial cancers and familial hypercholesterolemia. Clinical guidelines for these diseases recommend that cascade testing be offered to relatives of probands to identify cases [1–3]. Despite this, studies suggest that several genetic conditions remain underdiagnosed in the population [4–6], indicating that the implementation of cascade testing in clinical practice needs to be optimized.

To date, few studies have systematically reviewed the uptake of cascade testing in relatives of probands and the effectiveness of such interventions across various diseases. In a scoping review focused on the delivery of cascade testing for hereditary conditions, Roberts et al. provide a broad overview of cascade testing interventions, policy considerations, barriers and facilitators to their use and research gaps [7]. Based on their findings, several research gaps remain in the literature on cascade testing, including limited use of rigorous methods to test the efficacy of cascade testing programs and interventions. Understanding factors that influence whether probands disclose genetic information and whether relatives pursue genetic testing will be critical to design effective interventions to improve cascade testing. To address this need, we conducted an in-depth systematic review of the research literature to identify barriers and facilitators that may affect the uptake of cascade testing.

Methods information sources and search strategy

The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines [8] were followed for this study (Supplemental Material, Appendix A). The following databases: PubMed, CINAHL via EBSCO, Web of Science, EMBASE, and the Cochrane Library were electronically searched for articles published from the database inception date to 18 November, 2018 using keywords and appropriate subject headings that captured the range of terms used synonymously with cascade testing (e.g., “cascade screening” and “familial genetic testing”). Complete search strategies are provided in Supplemental Material, Appendix B. Hand-searches were also performed by manually examining the references of relevant literature reviews to identify any additional studies that may have been missed due to incomplete or inaccurate indexing in the electronic search databases. All references were uploaded to Covidence Systematic Review software (https://www.covidence.org) [9], a systematic review management system for study selection.

Study selection

Two of four reviewers (MCR, NYW, SS, and WDD) independently reviewed each title and abstract for eligibility, and disagreements were resolved through discussion. The same procedure was repeated for full-text review. Articles that focused on the disclosure of genetic information to family members and the actual uptake of genetic testing by relatives were both included to comprehensively capture barriers and facilitators to cascade testing both from probands’ and the family members’ perspectives. Conference abstracts, meeting reports, literature reviews, guidelines, and simulation modeling studies were excluded. Articles relating to other types of genetic testing and disclosure (whole-population or universal genetic testing, parental disclosure of genetic testing to children, newborn/neonatal/pre-natal testing, or proband testing), those that lacked a methods section or relevant outcomes (no barriers/facilitators described, study focused on clinical outcomes for cascade testing only, or study did not explicitly study cascade testing) and those that only reported prevalence of genetic testing were also excluded.

Data extraction and quality assessment

Data extraction forms were developed in Covidence using the PICOS framework for the following information: population (sample size and percentage of women), intervention (characteristics of the cascade testing intervention including disease area(s), whether counseling and resources related to cascade testing were provided, primary mediator of cascade testing), comparator (if applicable), outcomes (barriers and facilitators) and setting (country, scale, clinical, academic) [10]. Barriers and facilitators experienced either by proband or relatives in cascade testing were qualitatively described in some studies and, in others, were examined for their ability to predict relatives’ uptake of genetic testing or proband’s disclosure to relatives through methods like regression. Our coding used an inductive approach and reflected the language used by study authors. The forms were developed iteratively and piloted on a subset of five articles after which two reviewers independently extracted data from each study. Disagreements were resolved through discussion. Barriers and facilitators were organized according to the Social Ecological Model, a theoretical framework that allows for the examination of the interactions between personal and environmental factors on health behaviors [11].

The methodological quality of each study was assessed using the Mixed Method Appraisal Tool (MMAT), version 2018 [12]. Both reviewers independently assessed whether the study met the corresponding MMAT criteria for each study type (RCT, descriptive, observation, qualitative, or mixed-methods). Meta-analysis was not conducted given the significant heterogeneity in study design, populations, setting, and outcomes.

Results

Of the 4256 unique studies that were identified through database searching and hand-searching, 229 articles were assessed for full-text eligibility. Thirty articles [13–42] were included in our analysis after excluding articles as per the inclusion and exclusion criteria (see Fig. 1 for PRISMA flow diagram).

Fig. 1. PRISMA flow diagram.

Number of records identified, included and excluded in the systematic review, and reasons for exclusion.

Study characteristics for the included articles are available in Table 1. Twelve studies [13, 17, 22, 24–26, 28, 29, 35, 36, 38, 40] were conducted in the US while the remaining were conducted in Australia (n = 4) [14, 15, 19, 20], Europe (n = 9; 4 UK or parts of UK [23, 27, 31, 42], 4 Netherlands [21, 33, 34, 43], 1 France [39]), Asia (n = 4; 2 Israel [18, 41], 1 Vietnam [30], 1 Japan [16]), and South America (n = 1 from Brazil [37]). Most studies were conducted within a single-center (n = 12 [16, 17, 20, 22–24, 30, 34, 35, 37, 40, 41]), followed by national- (n = 10) [13, 14, 18, 21, 26, 29, 31, 33, 38, 43], regional- (n = 4) [19, 39, 40, 42], multi-center (n = 3) [27, 28, 36] and state- (n = 1) [25] level studies. The majority of studies (n = 18) [13, 14, 16–19, 25, 26, 28, 30, 33, 35–41] used a descriptive study design using survey/interview/case series/observational data, with a few qualitative studies (n = 9) [15, 21, 23, 24, 27, 29, 31, 42, 43] and mixed-method studies (n = 2) [20, 34] and one randomized controlled trial [22]. Studies spanned disease areas including familial hypercholesterolemia (n = 10) [13, 15, 19, 25, 30, 33, 35, 37, 42, 43], Lynch syndrome (n = 6) [16, 17, 21, 24, 28, 38], hereditary breast and ovarian cancer (n = 6) [18, 22, 29, 36, 40, 41], cystic fibrosis (n = 3) [20, 31, 39], inherited cardiac conditions (n = 2) [23, 27], Fragile X syndrome (n = 2) [26, 34], and long QT syndrome (n = 1) [14]. Only one study explicitly reported that counseling was included as a component of cascade testing [42], while two studies noted that resources to assist with cascade testing (letter, written material and information sheet) were provided to patients [23, 42]. In most studies, the stakeholder who contacted relatives was not explicitly defined (n = 16) [13, 14, 16, 18–21, 26–29, 31, 35, 36, 38, 39], with patients (n = 5) [22, 23, 34, 41, 44], study team members (n = 4) [24, 30, 40, 45], providers (n = 2) [17, 37] and members of a screening program (n = 3) [15, 33, 43] contacting relatives in the remaining studies. Three studies were conducted solely among women [13, 22, 36], one study was conducted solely among men [29], and six studies did not report the proportion of females in the study sample [20, 27, 30, 31, 34, 43]. Sixteen studies did not contain information about race and ethnicity of the study sample [14–16, 19–21, 23, 27, 30, 33, 34, 37, 39, 41–43, 45].

Table 1.

Study characteristics for included studies.

Study	Setting					Methods		Population			Intervention
	Year of study publication	Country	Setting	Year(s) of data collection	Scale	Design	Data Source	N (Study sample)	% White	% Female	Disease Area	Counseling related to cascade testing	Cascade testing primarily mediated by	Provision of resources related to cascade testing	MMAT Score
Benson13	2016	USA	Members of the WomenHeart and FH Foundation databases	2014	National	Descriptive	Survey data	761	86	100	Familial hypercholesterolemia	NR	NR	NR	4
Burns14	2015	Australia	Patients enrolled in the Australian Genetic Heart Disease Registry	NR	National	Descriptive	Survey data	75	NR	73	Long QT syndrome	NR	NR	NR	4
Campbell25	2017	USA	2014 Minnesota State Fair	2014	State	Descriptive	Survey data	971	NR	59	Familial hypercholesterolemia	NR	Study team	NR	3
Cheung20	2010	USA	Tertiary referral cancer center and public county hospital in California	1996–2008	Multi-center	Descriptive	Survey data	1135	60	100	Hereditary breast and ovarian cancer	NR	NR	NR	5
de Souza Silva21	2018	Brazil	Academic medical center	NR	Single-center	Descriptive	Survey data	183	NR	54	Familial hypercholesterolemia	NR	Provider (trained specialized health professional)	NR	3
Dilzell22	2014	USA	(1) Academic medical center, (2) patients affiliated with Lynch Sydnrome International, an advocacy group	2012–2013	National	Descriptive	Survey data	50	91	79	Lynch syndrome	NR	NR	NR	3
Dugueperoux23	2016	France	District in western Brittany where CF incidence is high	1980–2004	Regional	Descriptive	Observational data	128	NR	58	Cystic Fibrosis	NR	NR	NR	3
Finlay24	2008	USA	Academic medical center	2004	Single-center	Descriptive	Survey data	132	93	73	Hereditary breast and ovarian cancer	NR	Study team	NR	4
Hagoel25	2000	Israel	National cancer control center	NR	Single-center	Descriptive	Observational data	438	NR	70	Hereditary breast and ovarian cancer	NR	Patient	NR	4
Hallowell26	2011	Scotland	Regional cascade testing service	2010	Regional	Qualitative	Interview data	38	NR	55	Familial hypercholesterolemia	Yes	Patient	Yes (letters and written material)	3
Hardcastle15	2014	Australia	Lipid disorders clinic in Royal Hospital	NR	Regional	Qualitative	Interview data	18	NR	44	Familial hypercholesterolemia	NR	Screening program	NR	4
Ishii16	2011	Japan	Cancer Institute	2005–2009	Single-center	Descriptive	Survey data	40	NR	63	Lynch syndrome	NR	NR	NR	5
Lerman17	1999	USA	Academic medical center	1996–1998	Single-center	Descriptive	Survey data	139	99	55	Lynch syndrome	NR	Provider	NR	4
Lieberman18	2018	Israel	Medical center	NR	National	Descriptive	Survey data	1771	NR	79	Hereditary breast and ovarian cancer	NR	NR	NR	4
Maxwell19	2009	Australia	Western Australia	2008	Regional	Descriptive	Interview and survey data	430	NR	59	Familial hypercholesterolemia	NR	NR	NR	4
McClaren20	2013	Australia	Children’s Hospital	NR	Single-center	Mixed-methods	Interview data	249	NR	NR	Cystic fibrosis	NR	NR	NR	3
Mesters21	2005	Netherlands	Individuals enrolled in the Netherlands Foundation for the Detection of Hereditary Tumors	NR	National	Qualitative	Interview data	30	NR	73	Lynch syndrome	NR	NR	NR	5
Montgomery22	2013	USA	Fox Chase Cancer Center	2000–2003	Single-center	RCT	RCT data	422	92	100	Hereditary breast and ovarian cancer	NR	Patient	NR	4
Ormondroyd23	2014	UK	Academic medical center	2010–2011	Single-center	Qualitative	Interview data	22	NR	60	Inherited cardiac conditions	NR	Patient	Yes (invitation letter and information sheet)	5
Pentz24	2005	USA	Academic medical center	NR	Single-center	Qualitative	Interview data	80	85	65	Lynch syndrome	NR	Study team	NR	5
Raspa26	2006	USA	National survey research registry	2012	National	Descriptive	Survey data	679 families	92	90	Fragile X syndrome	NR	NR	NR	3
Smart27	2010	UK	Genetics Knowledge Park program	2005–2006	Multi-center	Qualitative	Interview data	27	NR	NR	Inherited cardiac conditions	NR	NR	NR	5
Stoffel28	2008	USA	Cancer genetics clinics in academic medical centers	NR	Multi-center	Descriptive	Survey data	174	91	70	Lynch syndrome	NR	NR	NR	4
Suttman29	2018	USA	Academic medical center	NR	National	Qualitative	Interview data	21	67	0	Hereditary breast and ovarian cancer	NR	NR	NR	5
Truong30	2018	Vietnam	Academic medical center	NR	Single-center	Descriptive	Case series data	112	NR	NR	Familial hypercholesterolemia	NR	Study team	NR	3
Ulph31	2015	England	Research university	2008	National	Qualitative	Interview data	67	68	NR	Cystic Fibrosis	NR	NR	NR	5
van El43	2018	Netherlands	Research university	NR	National	Qualitative	Interview data	6	NR	NR	Familial hypercholesterolemia	NR	Screening program	NR	5
van Maarle33	2001	Netherlands	Academic medical center	1998	National	Descriptive	Survey data	677	NR	54	Familial hypercholesterolemia	NR	Screening program	NR	5
Van Rijn34	1997	Netherlands	University hospital	1997	Single-center	Mixed-methods	Interview data	504	NR	NR	Fragile X Syndrome	NR	Patient	NR	3
Wurtmann35	2018	USA	Academic medical center	2016	Single-center	Descriptive	Survey data	38	89	87	Familial hypercholesterolemia	NR	NR	NR	3

Overall, both reviewers indicated that studies met three or more criteria, with few studies falling below this threshold. Barriers and facilitators at the individual, interpersonal and environmental levels are summarized in Tables 2 and 3, respectively. Notably, no studies in our analysis investigated any environmental facilitators. Only significant and descriptive results from our analysis are described below. In addition, nonsignificant factors are presented in Table 3.

Table 2.

Barriers to disclosure of genetic information and uptake of cascade testing at the individual level.

Barriers	Disclosure of Genetic Information to Relatives			Uptake of Genetic Testing by Relatives
	Probands only	Relatives only	Probands/ Relatives	Probands only	Relatives only	Probands/ Relatives
Individual barriers
Demographics
Income					Neg (Low)26
Knowledge
Knowledge/Perceived knowledge			Desc25			Qual23,27,31
Not knowing who was at risk in the family	Desc14,24
Reluctance to cause fear, stress, and negative emotions	Desc28			Desc18
Perceived susceptibility						Desc(Low)23
Attitudes, beliefs and emotional responses of the individual
Attitudes toward genetic testing						Desc23,27
Belief that costs outweigh benefits				Desc18
Lack of motivation						Qual15
Depression Symptoms	Neg (High)22			Neg (Present)17
Distress	NS22
General privacy concerns	Desc28		Desc25			Desc47
Deferment/rejection of responsibility		Desc35	Desc25			Qual15
Actionability of results			Desc25
Religion			Desc25
Discomfort with topic			Desc25
Embarrassment/Shame			Desc25,20			Desc31
Sadness			Desc25
Surprise			Desc25
Lack of trust			Desc25
Lazy			Desc25
Anxiety/Guilt	Desc14,28		Desc25,20			Desc27
Emotional or general difficulty in sharing information	Desc14,24	Desc35	Desc25
Logistical concerns		Desc35	Desc25	Qual26		Desc16
Fear of discrimination in the context of marriage or employment		Desc35		Desc18
Readiness for discussion				Desc18
Limited recall of diagnosis and competing pressures			Desc25,20			Qual27
No dissemination plan			Desc20
Paternalism						Desc47
Psychological burden						Desc47
Anticipation of regret						Desc33
Location of relatives			Desc25			Qual27
Time needed to communicate			Desc25
Prefer doctors to explain			Desc25
Perceptions of relatives, relatives’ reported responses, and attitudes toward relatives
Not wanting to upset relatives	Desc14	Desc35
No at-risk family members			Desc25
Relative lack of concern or interest			Desc25,20	Desc18
Relative not willing to listen /does not care	Qual24	Desc35	Desc25			Qual27
Relative hostility toward advice or rejection		Desc35	Desc25	Desc18
Relative did not believe participant			Desc25
Concern regarding family reaction			Desc25
Family lack of understanding	Qual24, Desc28	Desc35	Desc25,20
Family may not agree to testing			Desc25
Avoidance/Right not to know/Ignorance						Qual15, Desc20,33,47
Relatives’ stage of life			Desc20			Desc16, Qual27
Relative appears healthy						Desc16
Interpersonal barriers
Family communication, support and dynamics
Impact of disease on family				Desc34	Neg (Mostly or somewhat negative)26
Disappointing experience with disclosure early in process			Desc20			Desc31
Emotional distance or estrangement or conflict or resentment	Desc28		Qual21	Qual26, Desc18		Qual23,27
General communication concerns			Desc25	Neg (No communication)26, Desc34		Qual24,27
Not in contact/close with family	Desc24	Desc35	Desc25, Qual21			Desc16, Desc27
Language barrier			Desc25
Provider factors
Provider awareness				Qual29		Qual43
Provider engagement						Qual31
Environmental barriers
Accessibility of testing
Finances/Cost		Desc35	Desc25			Qual43
Insurance		Desc35	Desc25			Qual43
Access to genetic testing			Desc20			Qual31
Extra clinical referrals						Qual43

Neg – negative, Desc– barrier or facilitator described in descriptive studies, Qual- barrier or facilitator described in qualitative studies.

Table 3.

Facilitators for disclosure of genetic information and uptake of cascade testing at the individual level.

Facilitators	Disclosure of genetic information to relatives			Uptake of genetic testing by relatives
	Probands only	Relatives only	Probands/Relatives	Probands only	Relatives only	Probands/Relatives
Individual facilitators
Demographics
Age			Pos (High)20	NS13,21		NS20,17
Gender	NS28	Pos (Female)22				NS17, Pos (Female)23, Pos (Asian)20
Race/Ethnicity			Pos (Asian)20, NS (Latina)20, NS (African American)20	NS13		NS (Latina)20, NS (African American)20
Income				Pos (High)13		NS17
Education				NS21		Pos (College Degree)17
Employment				NS21
Marital Status				Pos (Married)13		Pos (Married)17
Socioeconomic status			NS20, Pos (High)20			Pos (High)20
Clinical factors
Personal history of disease	NS22,28			NS13,21		NS20,17, Pos25
Family history of disease				NS21
Smoking				NS13
Prior history of risk factors					Desc19
Genetic test results	Pos (unambiguous)22, NS (inconclusive)22
Knowledge
Knowledge/Perceived knowledge			Pos (High)20
Perceived susceptibility			Desc (High)21
Attitudes, beliefs and emotional responses of the individual
Distress	NS22
Wanting to know				Desc20		Desc33
Intrinsic motivation			Desc21
Perceived control	Pos (High)22
Forced by circumstances						Desc33
Need for emotional support	Qual24, Desc28	Desc35	Desc20	Desc18
Satisfaction with decision to undertake genetic testing			Pos (High)20			Pos (High)20
Perceptions of relatives, relatives’ reported responses, and attitudes toward relatives
Relatives’ right to know			Qual29	Desc34		Qual23, 24
Moral obligation toward relatives/Duty to inform		Desc35	Desc14,21	Desc18,26,34		Qual31
Feeling that information will help in making medical decisions or lifestyle		Desc35	Desc14			Qual27,31
Concern about relatives			Desc29	Desc20		Qual23
Desire to prevent harm in the family/Duty to protect		Desc35		Desc18		Qual15,27
Need to understand the disease/help from relatives	Desc28					Desc16
To avoid feeling the same sorrow						Desc16
Interpersonal facilitators
Family communication, support and dynamics
Perceptions of relatives’ opinion on genetic testing	Pos (Extremely or somewhat in favor)22, NS (Opposed/Neutral)22
Degree of closeness/Relationship to the patient		Pos (children)22, NS (siblings)22, Desc14				Pos (Siblings)23, Pos (Aunt/Uncles)23, NS (Grandparents)23, Pos (FDR of patient with disease)25, Pos (FDR of proband)25
Monitoring relatives’ coping status	NS22
Provide relatives with information about risk	Desc28		Desc14
Encourage relatives to get testing	Desc28		Desc14	Desc34
Active and open communication			Qual29
Solidarity with family						Desc33
Support from family members						Desc47
Provider factors
Materials to pass to relatives (Genetic counseling note, Family letter, Personal note from proband, Information/report from lab, Online resources, Support group information)		Desc35		Qual26		Desc22
Referral to genetics clinic						Desc22
Physician recommendation	Qual24, Desc28		Desc21			Desc16
Assistance in identifying relatives at risk		Desc35		Desc26
Assistance in making contact with relatives (physician or hospital) and dissemination plan		Desc35	Desc21			Qual15, 23,24
Provider follow-up						Desc47
Speaking with a genetic counselor		Desc35

Pos– positive, NS– not significant, Desc– barrier or facilitator described in descriptive studies, Qual- barrier or facilitator described in qualitative studies.

Individual barriers

Demographics

One study reported that having low income was negatively associated with uptake of genetic testing among relatives [26], while other studies reported positive associations with other demographic factors (presented under Facilitators).

Knowledge

Studies described low or perceived lack of knowledge among probands and/or relatives as a barrier for both disclosure [25] and uptake of testing [23, 27, 31]. Probands in two studies cited not knowing who was at risk for the disease as a barrier to disclosure [14, 40].

Attitudes, beliefs and emotional responses of the individual

A number of barriers for probands and/or relatives to disclosure were reported, including: actionability of results [25], religion [25], discomfort with topic [25], sadness [25], surprise [25], lack of trust in the genetic information presented [25], laziness [25], no dissemination plan [20], time needed to communicate [25], emotional or general difficulty in sharing information [14, 25, 35, 40], and a preference for doctors to explain [25]. Paternalism [43], psychological burden [43], anticipation of regret [33], location of relatives [27], low perceived susceptibility [23], attitudes toward genetic testing [23], and lack of motivation [15] were described by probands and/or relatives as barriers to uptake of genetic testing. High depression symptoms had a negative effect on disclosure by probands [22], while the presence of depression symptoms among probands had a negative association with uptake. A belief that costs outweighed benefits was described as a barrier to uptake by probands [17]. General privacy concerns [25, 28, 43], deferment or rejection of responsibility [15, 25, 35], anxiety or guilt [14, 20, 25, 27, 28], logistical concerns [16, 35, 44, 45], fear of discrimination in the context of marriage or employment [18, 35], and limited recall of diagnosis and competing pressures [20, 25, 27] were all described as barriers to disclosure and uptake by probands and/or relatives. Finally, lack of readiness for discussion among probands was described as barrier to uptake [18].

Perceptions of relatives, relatives’ reported responses, and attitudes toward relatives

Lack of concern or interest by relatives [18, 20, 25], the possibility of relatives not agreeing to testing [25], relatives not believing participants [25] and concern regarding family reaction [25] were described as barriers to disclosure among probands and/or relatives. Not wanting to upset relatives and family [14, 35], and lack of understanding [20, 25, 28, 35, 40] were described as barriers to disclosure among probands and/or relatives. Unwilling and uncaring attitudes of relatives [25, 27, 35, 40], relevance for relative’s stage of life [16, 20], and hostility toward advice or rejection [18, 25, 35] were described as barriers to disclosure and uptake among probands and/or relatives. Avoidance (or right not to know) [15, 20, 33, 43] and a perception that the relative appeared to be healthy [16] were barriers to uptake among probands and/or relatives.

Interpersonal barriers

Family communication, support, and dynamics

Emotional distance, estrangement, conflict, or resentment was described as a barrier among probands and/or relatives for both disclosure [21, 28] and uptake [18, 23, 42]. Similarly, not being in contact or not being emotionally close with family was described as a barrier among probands and/or relatives for both disclosure [21, 25, 35, 40] and uptake [16, 27]. General communication concerns was described as a barrier among probands and/or relatives for disclosure [25] and uptake [24, 27, 34]. In another study, no communication had a negative effect among probands on uptake of cascade testing [26]. A disappointing experience with disclosure early in the process was described as a barrier among probands and/or relatives for both disclosure [20] and uptake [31]. The impact on family relationship was described as a barrier among probands for disclosure [28]. The negative impact of disease on the family itself was described as a barrier among probands for uptake [34], and also reported to have a negative association among relatives for uptake [26]. Finally, language barriers among probands and/or relatives were barriers for disclosure [25].

Provider factors

Low provider awareness [29, 43] and lack of provider engagement [31] were described as barriers for probands and/or relatives for uptake of cascade testing.

Environmental barriers

Accessibility of genetic testing was the main environmental barrier studied in the literature. In two studies, probands and/or relatives described finances/cost [25, 43] or insurance coverage [25, 43] as barriers to both disclosure and genetic testing. In another study, relatives described finances, cost or insurance coverage as barriers to disclosure [35]. Access to genetic testing services was described as a barrier for probands and/or relatives for disclosure [20] and uptake [31]. Extra clinical referrals required to pursue genetic testing was also described as a barrier for probands and/or relatives for uptake [43].

Individual facilitators

Demographics

Older age was positively associated with disclosure among probands and/or relatives in one study [36]. Females had a positive association with disclosure (relatives) [22] and uptake of testing (proband and or relatives) [39]. Asian race of probands and/or relatives was positively associated with disclosure [36] and uptake [36]. Married individuals were more likely to engage both in disclosure (probands) [13] and uptake of testing (probands and/or relatives) [17]. High income of probands had a positive association with uptake of genetic testing by relatives in one study [13]. Last, high socioeconomic status of probands and/or relatives was associated with both disclosure and uptake of genetic testing in one study [36].

Clinical factors

Personal history of probands and/or relatives was positively associated with uptake [36] for probands and/or relatives in one study. Prior history of risk factors for relatives was described to be a facilitator for genetic testing [19]. Finally, receipt of unambiguous genetic test results by probands was positively associated with disclosure.

Attitudes, beliefs, and emotional responses of the individual

A need for emotional support from relatives was described as a facilitator in multiple studies for disclosure [20, 35, 40] and uptake [18] among both probands and/or relatives. A high satisfaction with the decision to undertake genetic testing was positively associated with both disclosure [36] and uptake [36] among both probands and/or relatives. Similarly, knowledge of screening and risk reduction recommendations was positively associated with disclosure among both probands and/or relatives [36]. Intrinsic motivation [21] and high levels of perceived susceptibility [21] were described as facilitators for disclosure among proband and/or relatives. In one study, high levels of perceived control [22] was positively associated with disclosure among probands. Lastly, probands and/or relatives indicated that feeling forced by circumstances [33] also enabled uptake of genetic testing.

Perceptions of relatives, relatives’ reported responses, and attitudes toward relatives

Prominently, a moral obligation toward relatives or a duty to inform was described in multiple studies as a facilitator for probands and/or relatives for both disclosure [14, 21, 35] and uptake [18, 31, 34, 42]. A desire to prevent harm in the family or duty to protect was described as a facilitator for probands and/or relatives for both disclosure [18, 35] and uptake [15, 27]. Relatives’ right to know (separate from duty to inform) [23, 24, 29, 34] and a belief that information would help in making medical or lifestyle decisions [14, 27, 31, 35] were also facilitators for probands and/or relatives for both disclosure and uptake. Concern for relatives was described as a facilitator for disclosure [29] and uptake [20, 23]. A perception of relatives having a positive opinion on genetic testing was positively associated with disclosure among probands. A need for help in understanding the disease was a facilitator for disclosure (probands) [28] and uptake (probands and/or relatives) [16]. A desire to prevent relatives from feeling the same sorrow [16] was also a facilitator for uptake among probands and/or relatives.

Interpersonal facilitators

Family communication, support, and dynamics

The degree of closeness was investigated in several studies. When the relatives were children, there was a positive effect on disclosure [22]. In one study, siblings, aunts and uncles were more likely to pursue genetic testing [39]. When the relatives were first-degree relatives of probands, there was a positive association with genetic testing [41]. Solidarity [33] and support [43] from family members were described as facilitators for uptake of genetic testing by probands and/or relatives. Encouraging relatives to get testing was described as a facilitator for disclosure (probands and/or relatives) [28] and uptake [34] (probands) [34]. Providing relatives with information about risk was described as a facilitator for disclosure among probands and/or relatives [14, 28]. Active and open communication was described as a facilitator for disclosure among probands and/or relatives [29].

Provider factors

Materials to pass to relatives (e.g., genetic counseling note, family letter) were described as facilitators for both disclosure (relatives) [35] and uptake (probands and/or relatives) [38, 42]. Assistance in identifying relatives at risk was described among probands as a facilitator for uptake [42], and among relatives for disclosure [35]. Assistance in making contact with relatives and a dissemination plan were described as facilitators for disclosure [21, 35] and uptake [15, 23, 24] among probands and/or relatives. A physician’s recommendation was described as a facilitator for both disclosure [21, 28, 40] and uptake [16] by probands and/or relatives. A referral to a genetics clinic [38] and provider follow-up [43] were described as facilitators for uptake among probands and/or relatives. Finally, speaking with a genetic counselor was described as a facilitator for disclosure by relatives [35].

Discussion

Several individual and interpersonal factors, and a few environmental factors, were described as barriers and facilitators to cascade testing for genetic conditions in studies included in our review. In particular, attitudes, beliefs and emotional responses both relating to the individual and their relatives were identified, with a large number of these factors reported in one study that used a survey design. Our findings suggest that there is a need to verify the role of these factors in the uptake of cascade testing using rigorous methods.

Factors relating to provider awareness and engagement were described as facilitators in included studies; conversely, lack of provider awareness and engagement were described as barriers in three studies. Previous studies evaluating cascade testing programs or interventions have shown that direct methods, where trained providers directly contact at-risk relatives of probands, are effective [46, 47]. Two studies [42, 43] included in this review examined the acceptability of direct vs. indirect approaches (where cascade testing is primarily patient-mediated) through qualitative methods, and findings from these studies indicate that even though direct methods may be more effective, patients expressed a preference for patient-mediated approaches as this emphasized autonomy and privacy, and was less threatening to relatives. Further, the regulatory landscape for provider-directed communication is not described in our included studies, and cannot be directly inferred (except in certain settings, such as the United States). Thus, the extracted facilitators from these two studies and others suggest several approaches for improving cascade testing in settings where a patient-mediated method is the norm, necessary (due to regulations) or preferred. In these settings, assistance in identifying at-risk relatives, creating a dissemination plan, receiving materials to pass on to relatives and follow-up were potential facilitators for cascade testing. These approaches could alleviate reported barriers regarding low or perceived lack of knowledge, as well as barriers such as not knowing who was at risk in the family.

Provider recommendation to share results with family was also described as a facilitator in several studies. This finding matches that of another study that examined non-directive approaches to counseling in families with BRCA1/2 gene variants, and suggested that more directive approaches are warranted in hereditary cancers, even if direct provider contact with relatives is not possible [48]. Overall, our results indicate that the role of the provider is critical in the process of cascade testing, and that the nature of provider engagement with patients and their relatives need to be optimized based on the environment and patient-preferences.

Family support, communication and dynamics play a key role in cascade testing, and several factors played a role either as barriers or facilitators. Indeed, it is well-known that genetic testing affects family relationships, with effects ranging from health benefits for relatives to strained relationships with family members. Interventions that strengthen family communication and increase family support, in addition to provider engagement, could optimize cascade testing. The process of genetic counseling typically incorporates psychosocial support for patients and their relatives, and interventions focused on enhancing family support and communication could be integrated in this process [49].

Our results also indicate that few studies have assessed factors outside the individual and interpersonal levels. In particular, contextual characteristics of the study setting and environmental barriers such as access to insurance, costs, etc. may be less relevant in countries with single payer-systems, but may play a more important role in countries such as the United States. Future work should examine the relative changeability and importance of multilevel barriers and facilitators for cascade testing. In addition it will be important not only to identify individual and interpersonal level determinants of cascade testing but also those on the environmental level (encompassing the organizational or institutional, community and public policy levels within the Social Ecological Model) to enable a comprehensive understanding of barriers and facilitators specific to various settings and contextual factors, as well as to build effective interventions.

Finally, studies across autosomal dominant and recessive disorders were included to capture barriers and facilitators to the process of cascade testing, whenever family communication and testing were explicitly studied. However, the motivation for cascade testing for variants that confer risk of developing disease (e.g., BRCA1/2 variants) versus those that confer risk for children inheriting a disease (e.g., cystic fibrosis) may drive the differences in the nature of individual and interpersonal barriers and facilitators described in our results.

Limitations

First, we performed a narrative synthesis of the literature, as a meta-analysis was not feasible given that studies in this area did not assess effect sizes of barriers and facilitators on cascade testing. Second, inconsistent terminology was used across studies for the factors investigated, so we were able to merge the extracted barriers and facilitators in only a few instances. Third, there is a potential for bias as we integrated findings from both quantitative and qualitative studies, a majority of studies used a descriptive study design, a majority of the barriers to disclosure were extracted from one study [25], and most of the non-demographic factors were described as barriers or facilitators, instead of being reported as effect-sizes. Fourth, as with any systematic review, it is possible that we may have missed relevant literature. Finally, from an ethical perspective, receiving all information necessary to make an informed decision about testing and being offered testing may be the most appropriate measures for evaluating interventions for cascade testing. However, we used family communication and receiving genetic testing as approximate outcomes, because many studies did not sufficiently discriminate between these distinct processes in outcome measurement. Thus, some barriers from our results (e.g., fear of negative impact on family relationships affecting uptake) may arise from receiving information about testing, being offered testing, but ultimately choosing not to engage in testing.

Conclusions

Findings from this systematic review can inform additional formative work. Future research should examine the role of identified barriers and facilitators for cascade testing using rigorous, theory-informed methods. Taken together this work can inform future development of interventions to improve cascade testing outcomes.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary information

The online version of this article (10.1038/s41431-020-00725-5) contains supplementary material, which is available to authorized users.