Colorectal cancer (CRC) is the second leading cause of cancer deaths in Canada and the United States. A positive family history (FH) significantly increases the risk of developing CRC, and screening programs can substantially reduce CRC incidence and mortality. These consensus recommendations were developed by the Canadian Association of Gastroenterology (CAG), with US and Canadian experts, and endorsed by the American Gastroenterological Association. The purpose was to systematically and critically review the literature and provide specific recommendations See editorial on page 1298.# 
BACKGROUND & AIMS: A family history (FH) of colorectal cancer (CRC) increases the risk of developing CRC. These consensus recommendations developed by the Canadian Association of Gastroenterology and endorsed by the American Gastroenterological Association, aim to provide guidance on screening these high-risk individuals. METHODS: Multiple parallel systematic review streams, informed by 10 literature searches, assembled evidence on 5 principal questions around the effect of an FH of CRC or adenomas on the risk of CRC, the age to initiate screening, and the optimal tests and testing intervals. The GRADE (Grading of Recommendation Assessment, Development and Evaluation) approach was used to develop the recommendations. RESULTS: Based on the evidence, the Consensus Group was able to strongly recommend CRC screening for all individuals with an FH of CRC or documented adenoma. However, because most of the evidence was very-low quality, the majority of the remaining statements were conditional ("we suggest"). Colonoscopy is suggested (recommended in individuals with 2 first-degree relatives ), with fecal immunochemical test as an alternative. The elevated risk associated with an FH of 1 FDRs with CRC or documented advanced adenoma suggests initiating screening at a younger age (eg, 40-50 years or 10 years younger than age of diagnosis of FDR). In addition, a shorter interval of every 5 years between screening tests was suggested for individuals with 2 FDRs, and every 5-10 years for those with FH of 1 FDR with CRC or documented advanced adenoma compared to average-risk individuals. Choosing screening parameters for an individual patient should consider the age of the affected FDR and local resources. It is suggested that individuals with an FH of 1 second-degree relatives only, or of nonadvanced adenoma or polyp of unknown histology, be screened according to averagerisk guidelines. CONCLUSIONS: The increased risk of CRC associated with an FH of CRC or advanced adenoma warrants more intense screening for CRC. Well-designed prospective studies are needed in order to make definitive evidence-based recommendations about the age to commence screening and appropriate interval between screening tests.
for CRC screening of individuals with an FH of nonhereditary CRC or adenoma. This is the first guideline to use systematic reviews and the GRADE (Grading of Recommendation Assessment, Development and Evaluation) approach to make recommendations for screening for CRC in this high-risk population. Multiple parallel systematic review streams, informed by 10 literature searches, assembled evidence on 5 principal questions: (1) effect of an FH of CRC on an individual's risk of CRC, (2) effect of an FH of adenoma on an individual's risk of CRC, (3) age at which screening should begin, (4) optimal screening tests, and (5) optimal testing intervals for individuals with an FH of CRC or adenoma. The GRADE approach was used to assess the quality of evidence. Questions were developed through an iterative online platform, and then statements were developed and voted on by a group of specialists.
Consensus was reached on 19 statements addressing 5 main patient risk categories, including individuals with 2 or more first-degree relative (FDRs) with CRC, 1 FDR with CRC, 1 or more FDRs with advanced adenoma, 1 or more seconddegree relatives (SDRs) with CRC, and 1 or more FDR with any non-advanced adenoma (Table 1).
Because of the lack of high-quality data, the majority of statements are conditional recommendations ("we suggest"). However, based on moderate-quality evidence, the Consensus Group is able to strongly recommend CRC screening over no screening for all individuals with an FH of CRC or documented adenoma. In addition, despite very-lowquality evidence, colonoscopy is recommended in individuals with 2 or more FDRs with CRC, because of the high-risk of life-threatening negative consequences of missed lesions.
Based on available data and consensus, Table 2 provides a concise summary of the preferred and secondchoice screening tests, the age at which screening should begin, and the interval for screening according to the level of elevated CRC risk for each patient subgroup. For individual at highest risk (2 or more FDRs with a history of CRC), we recommend screening with colonoscopy, which we suggest begin at age 40-50 years or 10 years younger than the age of diagnosis of the FDR (whichever is earlier), at an interval of every 5 years. For individuals with 1 FDR with a history of CRC or advanced adenoma, we suggest commencing CRC screening at age 40-50 years or 10 years younger than the age of diagnosis of the FDR (whichever is earlier), at an interval of every 5-10 years. For those with an FH of CRC, colonoscopy is suggested with fecal immunochemical test (FIT) as an alternative, while both tests are suggested options for those with an FH of advanced adenoma. Finally, it is suggested that individuals with an FH of 1 or more SDRs only, or of nonadvanced adenoma or polyp of unknown histology be screened according to average-risk guidelines.
Except for the statements for those at the highest risk, age ranges are provided. The relationship between the age at which an affected FDR was diagnosed with CRC and an individual's risk of developing CRC is difficult to define. The evidence shows that the risk falls on a continuum, and that there is no clearly defined age above or below which a clear inflection in risk can be recognized. The Consensus Group carefully considered the issue of recommending a range of years, acknowledging that some clinicians and programs may wish for greater precision. However, the evidence in cases where a range was recommended does not support a specific age point. Definitive statements in these circumstances are misleading and imply a degree of certainty that does not currently exist. Furthermore, specifying a range allows some flexibility, including consideration of the age of the affected FDR and local resources, and underscores the need for further data, which will hopefully lead to greater clarity in the future.
The Consensus Group acknowledged that heritable cancers tend to occur at an earlier age and that this heritable risk decreases with advancing age of the diagnosis of the CRC in the FDR. That being the case, the age of the affected relative should be considered when making clinical decisions regarding screening. For example, having an FDR diagnosed at 75-90 years of age is unlikely to seriously impact an individual's risk of CRC, while an FDR diagnosed at age 35 years is probably highly relevant. Therefore, we acknowledge that national or provincial programs may wish to set specific FDR age cutoffs for screening, based on additional factors, including feasibility, cost, and cost-effectiveness. From an evidence perspective, we are, unfortunately, not able to provide clear guidance at this time. Future research should prioritize prospective studies that assess the optimal time to initiate screening and appropriate intervals between screening tests.

# Introduction
Colorectal cancer (CRC) is the second leading cause of cancer in Canada, and the fourth leading cause in the United States. 1,2 It is the second leading cause of cancer deaths in both countries, with approximately 9400 Canadians, and 50,260 Americans dying of the disease annually. The 2017 estimated incidence of new cases CRC was 26,800 Canadians, and 135,430 Americans, and the prevalence of individuals living with CRC was 105,195 Canadians (2009) and 1.3 million Americans (2014). 1,2 A systematic review (SR) estimated the prevalence of an individual having 1 or more first-degree relatives (FDRs) with CRC to be 3%-10%, and of having 2 or more FDRs with CRC to be about 0.3%. 3 Many of these individuals with a positive family history (FH) are at an increased risk of developing CRC. However, the magnitude of the individual's increased risk appears to be dependent on the degree of relationship to the affected relative, age of the affected relative at time of diagnosis, and the age of the individual. Overall CRC burden in a family (ie, total number of individuals with CRC on the same side of the family) also increases the magnitude of the individual's CRC risk. This may be a red flag for an inherited CRC syndrome. 4 CRC usually develops from premalignant polyps, and CRC screening can be used to detect and remove these polyps or localized cancer. Evidence from studies conducted in individuals primarily at "average risk" for CRC shows that screening (with endoscopy or occult blood tests) can reduce CRC mortality and incidence.  Guidelines and the introduction of population-based screening programs have led to substantially increased uptake of CRC screening. Rates in the United States and Canada were about 25%-35% before 2003, but have increased to 55%-60% in 2012-2013 surveys. 8,9 Individuals with an FH of CRC are more likely to adhere to CRC screening recommendations compared to those with no FH. 3 But even among this higher-risk population, participation rates remain less than optimal. 3, While a variety of guidelines for screening individuals for CRC are available, the majority apply to patients at average risk,  or those at highest risk due to inherited germline mutations associated with CRC and polyposis. 4,23,24 The few guidelines that make detailed recommendations for screening individuals with an FH of CRC or adenoma have not systematically reviewed the literature in this specific population. 17,19,20 Recent guidelines from the US Multi-Society Task Force on CRC screening used a modified process to systematically review published literature on this topic, however, systematic assessments of the methodological quality of the individual studies were not presented, and the paper was published after our consensus meeting. 22 For this guideline, systematic literature searches were conducted and the quality of evidence (QoE) and strength of recommendations were rated using the Grading of Recommendation Assessment, Development, and Evaluation (GRADE) approach. 25 This guideline specifically excludes individuals with hereditary syndromes, such as Lynch syndrome, familial adenomatous polyposis, attenuated familial adenomatous polyposis, MUTYH-associated polyposis, Peutz-Jeghers syndrome, juvenile polyposis syndrome, Cowden syndrome, serrated (hyperplastic) polyposis syndrome, hereditary pancreatic cancer, and hereditary gastric cancer. However, hereditary CRCs occurring due to mutations and defects in certain genes account for about 5% of all CRC. 4 Given the substantial risk of CRC and extracolonic cancers warranting specific screening strategies, it is important to identify these patients with hereditary syndromes. The National Comprehensive Cancer Network proposed 9 recommendations (summarized in Table 3) for patients who should be referred to a genetics provider for further assessment of a hereditary cancer syndrome. In addition, many jurisdictions and hospitals have implemented universal screening programs for CRC and endometrial cancers that include microsatellite instability or immunohistochemistry to identify patients at risk of Lynch syndrome. These individuals should be managed according to appropriate guidelines for individuals with hereditary gastrointestinal cancer syndromes. 4,23,24 The purpose of this guideline was to systematically and critically review the literature and provide specific recommendations for CRC screening of individuals with an FH of nonhereditary CRC or adenoma.

# Methods

# Scope and Purpose
Questions around screening for CRC in individuals with an FH of nonhereditary CRC or adenomas were identified and discussed by the participants, aided by evidence derived from review of the literature on CRC screening. Specifically, the processes focused on 5 principal questions. 

# Sources, Literature Searches, and Systematic Reviews
Evidence for these consensus guidelines was gathered via multiple parallel SR streams. The SRs were informed by a series of 10 literature searches. The scope, search strategy, and yield of each literature search are shown in Supplementary Table 1. All SRs (and the corresponding metaanalyses, where applicable) were performed by the 2 GRADE methodologists (GL and FT), with one exception, an SR of prospective studies on the risk of CRC among individuals with an FH of CRC/adenoma vs those without, which was led by Ahmed M. Abou-Setta, with the data being independently confirmed by the GRADE methodologists. All searches, data extractions, and analyses were performed by 1 investigator and double-checked by a second investigator, with any disagreements resolved by consensus. Most of the literature searches supported more than 1 of the SRs, and most SRs depended on 2 or more literature searches. The streams of evidence and the research questions they addressed are briefly summarized in Table 4. The results of the SRs (along with the assessments of the QoE) were forwarded to the Consensus Group members 1 week before the face-to-face meeting.
All analyses were performed using the Cochrane Collaboration's Review Manager (RevMan).

# Assessment of the Quality of Evidence
The GRADE approach 25 was used by 2 nonvoting methodologists (GL, FT) to assess the following: risk of bias (of individual studies and overall, across studies), indirectness, inconsistency, imprecision, and other aspects (including publication bias) in order to determine the overall quality (trustworthiness) of evidence for each statement. As is described in GRADE 25,26 and used in prior Canadian Association of Gastroenterology (CAG) consensus documents,  the descriptors of high, moderate, low, or very low were used to grade the QoE for each statement. One week before the face-to-face meeting, the voting members of the CRC Consensus Group had access to the GRADE assessments (including evidence profiles, the results of the SRs and meta-analyses conducted for this guideline,   

# Consensus Process
The Consensus Group included 8 voting members: the meeting chair (DL), and 6 other gastroenterologists and clinical epidemiologists, as well as a family physician. The voting group included 2 participants from the United States (NJS, DAL). Nonvoting members included the moderator (JKM) and 2 GRADE methodologists (GIL, FT), 1 of whom acted as a co-moderator (GIL). The meeting was observed by members of the CAG and the Canadian Partnership Against Cancer. A patient advocate provided valuable insight during the initial guideline development.
A web-based platform (ECD solutions, Atlanta, GA) was used by the CAG to facilitate the consensus process before the 2-day face-to-face meeting held in Banff, Alberta, Canada in March 2017. Voting members used the platform to answer the principal questions to be addressed during the meeting and provided valuable comments, feedback, and suggested sources of evidence. All participants had access to the results of literature searches and relevant references.
At the meeting, the GRADE methodologists presented the data and provided the group with a review of the GRADE evaluations leading to the QoE determination for each of the questions. A modification of the Evidence-to-Decision (EtD) framework was applied to facilitate ranking of multiple screening methods for each specific population. The EtD framework is a formalized approach that enables a structured and transparent discussion on 12 criteria (is the problem a priority; how substantial are the desirable anticipated effects; how substantial are the undesirable anticipated effects; what is the overall certainty of the evidence on effects; is there important uncertainty about or variability in how much individuals value the main outcomes; do the desirable effects outweigh the undesirable effects; how large are the resource requirements; what is the certainty of evidence for the resource requirements; are the net benefits worth the incremental cost; what would be the impact on health equity; is the intervention/ option acceptable to key stakeholders; and is the intervention feasible to implement). 31 Recommendation statements were developed that were subsequently voted on anonymously via touchpads. If 75% of participants voted 4 (agree) or 5 Table 3.National Comprehensive Cancer Network Criteria for Further Genetic Risk Evaluation 4 Criteria Individuals meeting the revised Bethesda Guidelines Individuals with a family history that meets Amsterdam Criteria Individuals with colorectal (or endometrial) cancer with microsatellite instability or immunohistochemistry consistent with Lynch syndrome Individuals with papillary thyroid cancer that is the cribriform-morular variant, or hepatoblastoma Individuals with a diagnosis of CRC and >10 colorectal adenomas Individuals with a personal history of 20 adenomas Individuals with multiple gastrointestinal hamartomatous polyps or serrated polyposis syndrome Individuals from a family with a known hereditary syndrome associated with CRC with or without a known mutation Individuals with a desmoid tumor, multifocal or bilateral CHRPE CHRPE, congenital hypertrophy of retinal pigment epithelium. (strongly agree) on a scale of 1 to 5 (with 1, 2, and 3 indicating disagree strongly, disagree, and uncertain, respectively), a statement was then accepted. Once accepted, the "strength" of the recommendation (strong vs conditional) was determined based on 4 components: (1) QoE, (2) benefit-to-harm balance, (3) patients' values/preferences, and (4) resource requirements. 32 When the QoE was low or very low, unless at least 1 of the other 3 factors was overwhelmingly strong, the strength of the recommendation would typically default (without a vote) to "conditional," using the phrasing, "we suggest." If the QoE was moderate or high, the statement's strength was determined by an anonymous vote; if 75% of participants voted "strong, then the recommendation would be designated as "strong" and the phrasing was "we recommend."
The GRADE approach notes that a conditional recommendation should prompt clinicians to ". . . recognize that different choices will be appropriate for different patients and that they must help each patient to arrive at a management decision consistent with her or his values and preferences," whereas a strong recommendation is indicative of a more broadly applicable statement ("most patients should receive the recommended course of action"). 32 In accordance with CAG policy, written disclosures of any potential conflicts of interest for the 24 months before the consensus meeting were provided by all participants, reviewed by the CAG ethics committee, and made available to all group members.

# Canadian Association of Gastroenterology Approval and American Gastroenterological Association Endorsement
The chair (DL) and 1 of the GRADE methodologists (GL) initially drafted the manuscript, which was then reviewed and revised by the remaining members of the Consensus Group, both individually and jointly during a teleconference. The manuscript was then made available to all CAG members for comments for a 2-week period before submission for publication, as per CAG policy for all clinical practice guidelines.
Finally, the recommendations were reviewed, commented on, and endorsed by the American Gastroenterological Association.

# Role of the Funding Sources