Reporting Modifications from the IMPACT-FH Study Using the FRAME-IS Open Access

Familial hypercholesterolemia (FH), a genetic disorder that causes lifelong exposure to high LDL-cholesterol and often leads to atherosclerotic cardiovascular disease (ASCVD), can cause severe life-threatening outcomes such as heart attacks if not diagnosed and treated properly [1‒3]. There has been sub-optimal implementation of guideline-recommended cholesterol screening in childhood and young adults, leading to a lack of FH diagnosis and morbidity and mortality that could be prevented if cholesterol levels were reduced significantly early in life with sustained lipid-lowering therapy [4, 5]. There is an urgent need for widespread implementation of screening programs to reduce the burden on patients and the healthcare system caused by undetected and unmanaged FH.

The process of implementing evidence-based practices (EBPs), such as FH detection and treatment, varies across geographic locations/institutions and successful implementation of strategies will need to consider these different contexts [6, 7]. Implementation of programs or strategies in a healthcare setting different from where they were originally developed typically requires changes, or modifications, to improve the likelihood of success in the new setting [8, 9]. Such modifications have been used across systems and have been shown to improve implementation outcomes, for example, in chronic disease and HIV prevention programs [10‒13]. These modifications can be made proactively or in reaction to an unexpected challenge faced during the implementation process. Unfortunately, there has been a lack of adequate documentation of such modifications, causing a gap in understanding and evaluation of modifications in the dynamic process of implementation [14‒16]. The Framework for Reporting Adaptations and Modifications to Evidence-based Intervention Strategies (FRAME-IS) provides structure for documenting and evaluating the different ways that implementation strategies are modified while deploying EBPs into practice. The FRAME-IS includes four core modules to describe the modification, and systematically capture what is modified, the nature and goal of the modification, and the rationale for modifying. Three optional modules are also included to denote when the modification was made, who participated in the decision to modify, and how widespread the modification is. By using the FRAME-IS, implementers can better understand the impact of the modifications and ensure that EBPs are effectively adapted to fit local contexts and populations [17, 18].

The IMPACT-FH pragmatic research trial developed and tested a cascade testing program for at-risk relatives of patients with FH (i.e., probands) [19]. Cascade testing, the systematic screening of at-risk relatives, is an efficient and cost-effective way of identifying undiagnosed individuals with FH [7, 20‒23]. As part of the IMPACT-FH cascade testing program, we employed several implementation strategies including an informational packet, chatbots, and direct contact. These strategies were introduced to FH probands upon successful return of their genetic test results as options to share their results with at-risk relatives and improve cascade testing uptake.

Throughout the study, we utilized FRAME-IS to provide a framework for the study team to report modifications to the IMPACT-FH cascade testing program (intervention) and its implementation strategies. Informed by the FRAME-IS, we documented modification components including what was modified, the nature of the modification, primary goal and rationale for the modification, timing of the modification, participants in the modification decision-making process and how widespread the modification was. The aim of this manuscript was to define and explicate what processes and components needed to be modified for successful implementation of the IMPACT-FH cascade testing program and report on modifications that may be useful for other health systems and settings implementing similar programs or utilizing similar implementation strategies.

Probands included in this study were identified via Geisinger’s MyCode Community Health Initiative (MyCode^®) [24]. MyCode is a population-based genomics project that includes electronic health records (EHRs) and genomic data generated from exome sequencing. Patient-participants consent to have actionable genetic results, including FH, returned to them as part of a genomic screening initiative, called the MyCode GSC program [25]. When a variant is identified via exome sequencing, a sample is sent to a CLIA-certified genetics laboratory to be clinically confirmed at no cost to the patient-participant before the result is returned through the MyCode GSC program. A one-page family letter and chatbots were available to assist probands in sharing their results with relatives prior to the IMPACT-FH pragmatic research trial. These strategies were optimized and a direct contact program was created based on feedback from FH probands and their relatives obtained during the pre-implementation phase of the IMPACT-FH study [26]. The IMPACT-FH cascade testing program, which included study follow-up calls and the three optimized implementation strategies to help facilitate family communication and cascade testing of at-risk relatives, was introduced to patient-participants receiving an FH result from the MyCode GSC program (defined as the proband for this study) upon successful return of their genetically confirmed FH result. The implementation strategies included were the Family and Healthcare Professional (HCP) Packet, the Family Sharing and Cascade Chatbots, and the FH Outreach and Support Program (Table 1 [19]). Probands were provided information on all implementation strategies and were able to choose which strategy or combination of strategies to use for each of their relatives. Study follow-up phone calls were conducted by a research assistant at 1, 6, and 12 months after the return of the proband’s FH result with the purpose of further discussing the implementation strategies and collecting data on strategy selection and cascade testing uptake.

The Family and HCP Packets were provided for the proband to share with their relatives. The physical or electronic packet contains an informational letter to the relative about the proband’s result and detailed instructions on how to pursue genetic and cholesterol cascade testing, a letter for the relative to give to their HCP that included similar information but using more medical vocabulary, and a copy of the proband’s laboratory report of their FH genetic result.

The Family Sharing Chatbot (FSC) is a HIPAA-compliant web-based conversational tool that probands receive via a link which they can utilize to send a separate Cascade Chatbot (CC) link to their relatives. The CC provides relatives with information about the proband’s FH result, their own FH risk, and options for pursuing genetic and cholesterol cascade testing. Relatives could use the CC to order a mail-in genetic testing kit for USD 20 within a 150-day window set by the genetic testing laboratory.

The FH Outreach and Support Program involves a genetic counselor directly contacting a proband’s relative and/or relative’s HCP. When this outreach was requested by the proband, the study team collected the applicable contact information and obtained verbal HIPAA authorization, allowing them to share information about the proband’s FH result with the selected individuals. If contacting the proband’s relative, the study team advised the proband to give their relative a “heads-up” that they would be contacted and sent a physical or electronic “primer” letter, which allowed the relative to opt out of the direct contact with the genetic counselor. A primer letter was not sent when direct contact was selected for the relative’s HCP. The genetic counselor made three attempts to reach the designated relative and/or HCP via phone to discuss the proband’s FH result, the relative’s risk, and options for genetic and cholesterol cascade testing. Depending on where the relative lived, the genetic counselor was able to order genetic cascade testing during the direct contact call and/or send the CC to allow relatives to order the mail-in genetic testing kit, if the relative desired.

Prior to the enrollment of participants, the study team decided to assess modifications to the IMPACT-FH cascade testing program and its implementation strategies using the FRAME-IS [17, 18]. The FRAME-IS contains all components of the FRAME and supplement components related to implementation strategies. All study team meetings were recorded, and detailed minutes were taken to capture discussions of and decisions on modifications made throughout the implementation of the IMPACT-FH cascade testing program. Interviews were also conducted with 15 probands, 12 relatives, and 6 healthcare professionals (4 genetic counselors, 1 research assistant, and 1 genetic counseling assistant) from the IMPACT-FH team to assess implementation outcomes including acceptability, appropriateness, feasibility, adoption, and fidelity. Interviews were transcribed verbatim and thematic analysis was used to analyze the interview transcripts. This manuscript reports interview data related only to fidelity; all other implementation outcomes have been reported separately [27]. Modifications were documented according to the FRAME-IS components for the overall IMPACT-FH cascade testing program and each implementation strategy [17, 18].

All modifications were initiated during the implementation phase of the study and were unplanned/reactive (Fig. 1-3). Overall, modifications were made to the IMPACT-FH cascade testing program (Fig. 1), FSC and CC (Fig. 2), and the FH Outreach and Support Program (Fig. 3). No modifications were made to the Family and HCP Packet.

Three modifications were made to the IMPACT-FH cascade testing program. First, a content modification was made to simplify the implementation strategy names when discussing them with probands. This modification was made with the goal of increasing the reach of the cascade testing program. Rather than using the formal names for the strategies during every interaction, members of the study team referred to the Family and HCP Packet as the “packet,” the FSC and CC as the “chatbots,” and the FH Outreach and Support program as “having a genetic counselor reach out.” This resulted in more streamlined discussions where the strategies were more easily understood by probands.

Second, there was a context modification made to the format of the 1-month study follow-up phone calls. These calls were originally planned to be only cold calls, where the study team would make three attempts to contact the proband starting 1 month after the return of their FH result to further discuss the IMPACT-FH cascade testing program. A modification made was to provide probands the additional option of scheduling their 1-month follow-up phone call for a specific date and time. This option was offered to probands during the return of their FH result and/or during their genetic counseling visit if that took place before the 1-month timepoint. This modification was made to increase the reach of the IMPACT-FH cascade testing program by being able to successfully discuss the program and strategies with more probands at that timepoint. It was also made to increase the acceptability and efficiency of follow-up calls; probands were able to schedule a date and time that worked for them, and study staff had to make fewer contact attempts.

Third, another context modification was made to the population of probands who received the IMPACT-FH cascade testing program. The genetic testing laboratory that was clinically confirming the probands’ FH results began experiencing technical issues during this study that led to an increased risk of sample failure. To accommodate this and limit the impact on the study timeline, the study team temporarily slowed and later paused sending samples to this laboratory for confirmation. This decision was made because there was a limited supply of DNA samples that could be sent for confirmation and in some cases, if the sample failed, there would not be enough DNA to send a second sample, resulting in the inability to clinically confirm the result for return to the proband. This pause led to a period in which results were not returned to probands (cessation of the program) or were clinically confirmed at another genetic testing laboratory (probands not eligible for the program). Once the issue was resolved, the study team increased the number of samples sent for confirmation beyond what had been originally anticipated to make up for the time lost during the pause and to include as many probands as possible in the study. Therefore, this modification was made to preserve the ability to evaluate the cascade testing program and the implementation strategies.

Three modifications were made to the FSC and CC. First, a content modification was made to the workflows and timelines for the FSC and CC due to technical issues. In relation to the FSC, the first invitation was supposed to be automatically sent to probands the day after their FH result was returned. Probands had a choice of receiving this invitation by email, text, or patient EHR portal message. During the study, there was a technical issue with the chatbot platform that prevented the automated invitation messages from being sent via text message for a short time. Therefore, the study team manually triggered the sending of the text messages once the issue was identified, which led to several probands receiving their invitations later than planned. In relation to the CC, there was a disruption in the workflow for sending the mail-in genetic testing kit after relatives ordered the test kit within the CC. Once a relative ordered the genetic testing kit in the CC, an automated notification was supposed to be sent to the genetic laboratory’s team alerting them to the order and mailing the kit to the relative within three business days. It came to the study team’s attention that this notification had been removed during an update to the chatbot platform, which led to a delay in orders being placed and relatives receiving their genetic testing kits later than planned. Therefore, the automated notification was reactivated, and the laboratory ensured that all testing kits were mailed. Manually sending the FSC text message invites to probands and correcting the CC test kit notifications were modifications made to fix a breakdown in fidelity.

Second, a content modification was made to the CC that allowed additional data elements from the proband’s EHR to automatically flow into the chatbot platform and CC messages. The study team realized that data elements needed for the optimized CC to function as intended for relatives ordering their mail-in genetic testing kit, such as the proband’s laboratory name, test requisition number, and report date, were not appearing. Return of FH results to probands was paused for a short period of time to limit the number of relatives utilizing the CC during this time. Return of results resumed shortly after the additional data elements were added and functionality was restored. As a result, a total of 30 relatives placed an order for a mail-in genetic testing kit via the CC. This modification was made so that relatives were able to use the CC as intended, with the goal of improving fidelity.

Third, a modification to the return of results workflow was made to confirm the proband’s contact information for receiving the FSC and manually update or input missing contact information into the chatbot platform if needed. When introducing the chatbot to the proband, the study staff (usually a genetic counselor) would ask the proband if they preferred to receive the FSC by email, text, or patient EHR portal message. The chosen contact method information would normally flow from the EHR to the chatbot platform and trigger the sending of the FSC invite to the proband. After a case where the proband did not have the relevant contact information within their EHR, the study team decided to add this confirmation step to ensure that probands received the FSC invite on time and via their preferred method. Therefore, this modification was also made to improve fidelity.

Five modifications were made to the FH Outreach and Support Program. First, a content modification was made, in response to relatives’ requests, to allow at-risk adult relatives to have genetic testing ordered for their minor child(ren) during their direct contact call with one of the study team’s genetic counselors. Parents were anxious about their child’s FH status and wanted their child to receive the appropriate care as soon as possible if found to have FH, and a delay in cascade testing could lead to a delay in their child’s care. Rather than waiting for the relative’s own cascade testing result to come back and then having to complete additional steps to order genetic testing for their child(ren) as was initially planned, the program was revised to facilitate testing of both the adult relative and their minor child(ren) at the same time. The FH Outreach and Support program was not intended to be selected for minors and a separate primer letter was not sent to the child(ren), but the genetic counselors did engage the child(ren) in the adult relative’s phone discussion when appropriate. This change did not impact the study’s ethics approval as it was originally planned that minors would receive cascade testing through the program. This modification led to completion of cascade testing in four minor children. The study team made this decision to increase the reach of the IMPACT-FH cascade testing program, as well as to be more patient-centered and beneficent.

Second, a content modification was made to tailor the FH Outreach and Support Program workflow for a proband’s incarcerated relative. A proband selected the FH Outreach and Support program for their incarcerated relative’s HCP and provided the contact information for the facility so that the study team could directly contact the appropriate medical staff. The study team initially followed the standard workflow for direct contact with a relative’s HCP, in which a genetic counselor would make three phone call attempts to speak with the HCP. However, after these attempts to reach the incarcerated relative’s HCP via phone were unsuccessful, the study team developed a packet of information which was mailed to the relative’s HCP at the facility. Cascade testing was not reported as being completed for this relative. This modification was made with the goal of increasing the reach by making an additional attempt to contact the relative’s HCP and increasing the health equity/decreasing disparities so as not to prevent the incarcerated relative from receiving this important risk information about FH due to the phone calls being unanswered.

Third, a content modification was made to the FH Outreach and Support Program’s primer letter in which it was translated from English to Russian using the hospital’s approved services. A proband selected the FH Outreach and Support Program for their relative but noted that their preferred language was Russian; therefore, the study team decided to have the primer letter translated and proceed with the standard direct contact workflow. In this case, the genetic counselor made phone outreach attempts with the hospital’s translation services on the line. This outreach was unsuccessful, and cascade testing was not reported as completed for this relative. However, this modification was made with the goal of increasing the reach of the IMPACT-FH cascade testing program and to increase the health equity/decrease disparities by not preventing probands from selecting the FH Outreach and Support Program for relatives with preferred language other than English.

Fourth, a content modification was made to specify that in situations where the proband selected the FH Outreach and Support Program for multiple at-risk adult relatives within the same household, the study team would send each relative their own individual primer letter and not a single letter addressed to multiple relatives. This ensured that relatives did not have to communicate with one another about the primer letter or any of its contents and could independently decide whether to participate in direct contact. This modification was made to improve fidelity to the IMPACT-FH cascade testing program.

Finally, a content modification was made to forgo the 14-day waiting period in between sending FH Outreach and Support Program’s primer letter and the first phone outreach attempt in cases where the proband advised the study team that their relative(s) were already made aware of and were agreeable to the direct contact. While all probands were advised by the study team to give their relative(s) a “heads-up” when selecting direct contact for them, some probands had already done so prior to the discussion with the study team and formal selection of the strategy for that relative. This meant that the relative could be contacted by the study team’s genetic counselor and have cascade testing ordered more quickly, which was particularly helpful in situations where the laboratory’s 150-day “free” cascade testing window was close to expiring. As a result, one relative completed cascade testing. This modification was made to increase the reach and the fit of the IMPACT-FH cascade testing program as relatives were expecting direct contact.

Implementation science, when used effectively, can be a useful tool for increasing the uptake of interventions and EBPs [28]. Identifying implementation strategies that contribute to improved outcomes is essential, and components of these strategies often can or need to be changed to further enhance outcomes. Using the FRAME-IS provides enhanced documentation of such modifications, which increases transparency, fosters collaboration and understanding among researchers implementing similar programs, and allows for better evaluation of the impact of the strategies. In this study, we report on modifications that contributed to the successful implementation of the IMPACT-FH cascade testing program and its three implementation strategies. All modifications were uniquely tailored to the IMPACT-FH pragmatic research trial design and setting, demonstrating the need for the use of modifications in implementation efforts across varying geographic locations and institutions [10]. Several modifications made throughout this program were necessary to maintain flexibility in proband and relative contact methods, maximizing overall reach and improving fidelity by meeting the needs of our population. Listening to and absorbing the feedback from probands and relatives directly led to many of our modifications, such as allowing additional genetic test ordering during direct contact. Such modifications can improve study or program outcomes as well as public health outcomes. As the type and general purpose of many of these are likely to be generalizable to multiple settings, using the FRAME-IS to standardize our reporting of these modifications could provide key insights into what other stakeholders could anticipate and methods for adapting to institutional needs as similar programs are implemented.

Often, modifications are necessary to improve health equity and bridge healthcare gaps, as seen in this study. For example, incarcerated populations have been historically shown to experience a greater burden of diseases and more severe outcomes compared to non-incarcerated individuals, which is particularly concerning as prison populations are growing in age and healthcare needs [29‒31]. Here, we had one relative in our study who was incarcerated, resulting in unique challenges related to directly contacting their HCP or eliciting the HCP’s interest in this cascade testing program. To address this gap, an informational packet was tailored to uniquely meet these needs and was mailed to the institution rather than relying on direct phone calls. Further, language barriers can lead to poor health outcomes and overall dissatisfaction with the healthcare system [32, 33]. To ensure equity in FH screening, we modified our program to include appropriate translation services for individuals whose preferred language was not English. While this approach was feasible in the context of the IMPACT-FH study due to the translation resources that were readily available within the healthcare system, it may not be available in other systems or settings. Finally, the significant costs related to healthcare have been observed as a major barrier to pursuing prompt medical care, with socioeconomic status predicting worse outcomes [34, 35]. Reduction of medical costs can help mitigate this barrier. In this program, there was an opportunistic window during which screening was free or low-cost for at-risk relatives. To adhere to this window and reduce the cost burden for more relatives, we eliminated the 14-day waiting period, which allowed for more prompt communication and testing turnaround. In many cases, this free or low-cost testing was a motivating incentive to complete testing that otherwise may not have been completed.

Open communication and feedback loops among researchers, practitioners, and patients and families (i.e., end users of an intervention) are vital to modifying implementation strategies in an effective way. By maintaining our flexibility throughout this study, we were able to increase our reach to marginalized populations and ensure that we were acting in a patient-centered manner to improve FH identification. This was partly due to our pragmatic research trial design, which was selected specifically for its ability to shift to the needs of the probands and relatives throughout the study [36]. Recent work demonstrated the advantages of adapting to circumstances during the highly challenging time of the COVID-19 pandemic [37].

With this study we demonstrate that FRAME-IS can be useful in healthcare settings during the implementation of EBPs, particularly for illuminating modifications necessary to improve the reach and equity of the EBP. Several of the modifications made also led to increased uptake of the EBP by prompting cascade testing that may have not otherwise been ordered for and completed by at-risk relatives. Using the FRAME-IS helped ensure that our modifications were systematically recorded and evaluated to understand their impact on improving implementation outcomes, particularly fidelity, within our setting. Sharing these modifications may help other researchers modify and adapt similar programs and implementation strategies to fit their local contexts and populations, leading to a more effective and sustainable implementation of EBPs.

The authors thank the individuals who participated in the interviews for this project.

This study was approved by the Geisinger Institutional Review Board (IRB #2019-0574). Written informed consent was not obtained for participation in this study. Verbal informed consent was obtained for participation in this study. This protocol was approved by the Geisinger Institutional Review Board (IRB #2019-0574). All procedures performed in studies involving human participants were in accordance with the ethical standard of the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Amy C. Sturm is an employee and stockholder of 23andMe and serves on the Advisory Board for Nest Genomics. Laney K. Jones is a consultant for Novartis. Mary P. McGowan participated in the Novartis Advisory Board. Nest Genomics, 23andMe, and Novartis had no involvement in the conceptualization of research; study design and conduct; collection, management, analysis, and interpretation of data; writing and reviewing the manuscript; or the decision to submit the article for publication.

This work was supported by the National Heart, Lung, And Blood Institute of the National Institutes of Health (Grant No. R01HL148246, 2024).

All authors have read and approved the manuscript. Conceptualization, investigation, and writing – original draft: C.G.K., N.L.W., G.C.-S., and L.K.J. Data curation and formal analysis: N.L.W., A.B., A.K.R., and L.K.J. Funding acquisition: A.C.S., A.K.R., and L.K.J. Methodology: N.L.W., A.B., and L.K.J. Project administration and resources: N.L.W. and A.B. Writing – review and editing: C.G.K., N.L.W., G.C.-S., L.K.J., A.K.R., A.B., A.C.S., and M.P.M.

Christie Gilbert Klaczko and Nicole L. Walters contributed equally to this work.

The datasets analyzed during the current study are not publicly available due to protecting participant privacy but are available from the corresponding author on a reasonable request.