Basic reporting

The authors do not provide information about the educational level of participants (in demographics Table 1), which would be useful if available.

Is there information on which participants had children? This would be helpful to interpret the results regarding men’s concerns about passing mutations to their daughters. Did these men already have children? What about the women?

Experimental design

The authors do not specify what type of software (if any) was used to code and analyze the data.

The authors also do not specify how the four coders 'reconciled' their coding. Can they provide intercoder reliability scores (if used), or further information on how reconciliation was achieved?

Validity of the findings

This article makes an important contribution to the literature by providing much needed empirical evidence from individuals who have received 'high impact' genetic information via DTC testing. While the data is encouraging, the small sample size and broad conclusion that population wide screening should be considered require further qualifications. Therefore my main comments are in relation to the discussion and conclusions drawn, and I suggest the authors acknowledge/address the issues below more fully:

1. The evidence does indicate that there did not appear to be detrimental emotional effects for the individuals who received mutation positive results, however it is important to note that many of the carriers (22/32) had family histories, had already been tested, had cancer themselves...etc and therefore were aware of their increased risk prior to testing. It is likely that this pre-existing sense of risk helped prepare them for results and led to less stress or shock. Those individuals who are completely unprepared or unaware of their risk may find results more distressing as indicated by the fact that 3 out of 4 who were ‘moderately upset’ were not expecting the results and reported feeling shock or surprise. If the author’s recommendation is population wide screening, more research is required about the implications for individuals who are completely unprepared.

2. The authors note that 23andMe customers are not representative of the population. More should be said here, in particular regarding the fact that this may be a very unique, proactive, and highly educated group (it would be nice to see information on educational level if available) that does not necessarily reflect the larger population.

3. The authors note that BRCA mutation testing is valuable because it is clinically actionable. This is true, however it is important not to understate the difficult decisions and deliberations for women considering undergoing prophylactic bilateral mastectomy and oophorectomy (especially at a young age). There remain considerable uncertainties about the effectiveness of screening (MRI vs mammography, ovarian screening) especially for women below 25. If population screening is being recommended, it is likely more young women will be tested and these women may find the available options more difficult to cope with emotionally.

4. The authors report the surprising and 'remarkable' number of carriers who reported feeling 'neutral' after receiving their mutation positive results. There does not appear to be enough evidence to determine if individuals were indeed 'neutral' or if these were the individuals who already were known mutation carriers, had strong family histories, or perhaps felt no change to their pre-existing feelings which are unknown.

5. One of the concerns about DTC testing is that it will put an undue burden on healthcare system (as mentioned by the authors in the introduction). This needs to be addressed further, as 60% of individuals who were mutation carriers did seek further medical advice and are advised to do so by 23andMe. The authors suggest that this high number may be related to the actionability of the results, however this may put a strain on the health care system especially if population wide screening is being recommended.

6. Related to the point above, it would be useful for the authors to address the fact that physicians were not necessarily prepared to handle DTC information, gave inappropriate advice, or did not know what to do with the reports. This points to a need for physician education as well.

7. The authors touch upon, but do not go any further, in discussing the presence of these mutations in non-Ashkenazi individuals, and the deficiencies of using self identified Ashkenazi ancestry to determine who should be tested. Do the authors have a suggestion for how to deal with this? Do they suggest testing all individuals in the population, only self-identified Ashkenazi Jewish individuals, Sephardi Jews as well…etc? This also relates to an additional, and unaddressed, point regarding the fact that other populations, such as Latino/as and African Americans may not benefit from this population screening despite the fact that they may also carry particular founder mutations. Is there potential to increase health disparities?

8. The authors suggest that the results of this study will be important especially as whole genome/exome sequencing is increasingly available. This study does provide important data about individual responses to DTC testing for serious genetic conditions, however BRCA testing is significantly different from much of the information that is currently available from whole genome/exome studies where results may be of unknown significance or create a very small and multi-factorial increased risk. BRCA mutations are highly penetrant and transmitted in an autosomal dominant fashion, and management options are available. The authors could make this distinction more explicit.

9.The authors report that males, rather than females, had greater concern about passing on mutations to their daughters. This interpretation appears overly simplistic. There is increasing literature about the impact of mutation status on reproductive decision making for women (Ormondroyd et al, Julian-Reynier et al 2012, Fortuny et al 2009). I think it is slightly misguided to conclude that this is a greater concern for men than women. Rather I think it is the primary or initial concern for men who do not have to consider risk management options for breast/ovarian cancer, whereas women are faced with their own risk management as well as their children’s risks.

10. The fact that men were less likely to seek advice from a physician than women and felt uncomfortable sharing information with relatives speaks to a common and recognized ‘gendered’ burden of health care and sharing of information which often falls to women.

Comments for the author

This article makes an important contribution to the literature by providing much needed empirical evidence from individuals who have received 'high impact' genetic information via DTC testing. While the data is encouraging, the small sample size and broad conclusion that population wide screening should be considered require further qualifications. Therefore my main comments are in relation to the discussion and conclusions drawn, and I suggest the authors acknowledge/address the issues below more fully:

1. The evidence does indicate that there did not appear to be detrimental emotional effects for the individuals who received mutation positive results, however it is important to note that many of the carriers (22/32) had family histories, had already been tested, had cancer themselves...etc and therefore were aware of their increased risk prior to testing. It is likely that this pre-existing sense of risk helped prepare them for results and led to less stress or shock. Those individuals who are completely unprepared or unaware of their risk may find results more distressing as indicated by the fact that 3 out of 4 who were ‘moderately upset’ were not expecting the results and reported feeling shock or surprise. If the author’s recommendation is population wide screening, more research is required about the implications for individuals who are completely unprepared.

2. The authors note that 23andMe customers are not representative of the population. More should be said here, in particular regarding the fact that this may be a very unique, proactive, and highly educated group (it would be nice to see information on educational level if available) that does not necessarily reflect the larger population.

3. The authors note that BRCA mutation testing is valuable because it is clinically actionable. This is true, however it is important not to understate the difficult decisions and deliberations for women considering undergoing prophylactic bilateral mastectomy and oophorectomy (especially at a young age). There remain considerable uncertainties about the effectiveness of screening (MRI vs mammography, ovarian screening) especially for women below 25. If population screening is being recommended, it is likely more young women will be tested and these women may find the available options more difficult to cope with emotionally.

4. The authors report the surprising and 'remarkable' number of carriers who reported feeling 'neutral' after receiving their mutation positive results. There does not appear to be enough evidence to determine if individuals were indeed 'neutral' or if these were the individuals who already were known mutation carriers, had strong family histories, or perhaps felt no change to their pre-existing feelings which are unknown.

5. One of the concerns about DTC testing is that it will put an undue burden on healthcare system (as mentioned by the authors in the introduction). This needs to be addressed further, as 60% of individuals who were mutation carriers did seek further medical advice and are advised to do so by 23andMe. The authors suggest that this high number may be related to the actionability of the results, however this may put a strain on the health care system especially if population wide screening is being recommended.

6. Related to the point above, it would be useful for the authors to address the fact that physicians were not necessarily prepared to handle DTC information, gave inappropriate advice, or did not know what to do with the reports. This points to a need for physician education as well.

7. The authors touch upon, but do not go any further, in discussing the presence of these mutations in non-Ashkenazi individuals, and the deficiencies of using self identified Ashkenazi ancestry to determine who should be tested. Do the authors have a suggestion for how to deal with this? Do they suggest testing all individuals in the population, only self-identified Ashkenazi Jewish individuals, Sephardi Jews as well…etc? This also relates to an additional, and unaddressed, point regarding the fact that other populations, such as Latino/as and African Americans may not benefit from this population screening despite the fact that they may also carry particular founder mutations. Is there potential to increase health disparities?

8. The authors suggest that the results of this study will be important especially as whole genome/exome sequencing is increasingly available. This study does provide important data about individual responses to DTC testing for serious genetic conditions, however BRCA testing is significantly different from much of the information that is currently available from whole genome/exome studies where results may be of unknown significance or create a very small and multi-factorial increased risk. BRCA mutations are highly penetrant and transmitted in an autosomal dominant fashion, and management options are available. The authors could make this distinction more explicit.

9.The authors report that males, rather than females, had greater concern about passing on mutations to their daughters. This interpretation appears overly simplistic. There is increasing literature about the impact of mutation status on reproductive decision making for women (Ormondroyd et al, Julian-Reynier et al 2012, Fortuny et al 2009). I think it is slightly misguided to conclude that this is a greater concern for men than women. Rather I think it is the primary or initial concern for men who do not have to consider risk management options for breast/ovarian cancer, whereas women are faced with their own risk management as well as their children’s risks.

1. The fact that men were less likely to seek advice from a physician than women and felt uncomfortable sharing information with relatives speaks to a common and recognized ‘gendered’ burden of health care and sharing of information which often falls to women.