What's out there for parents? A systematic review of online information about prenatal microarray and exome sequencing

Abstract Objective To identify what online patient information (presented in English) is available to parents about prenatal microarray (CMA) and exome sequencing (ES), and evaluate its content, quality, and readability. Method Systematic searches (Google and Bing) were conducted, and websites were categorised according to their purpose. Websites categorised as patient information were included if they were: in English, directed at patients, or were a text, video, or online version of an information leaflet. Author‐developed content checklists, the DISCERN Genetics tool, and readability tests (the Flesch Reading Ease Score, the Gunning Fog Index, and the Simple Measure of Gobbledygook Index) were then used to assess those sources of patient information. Results Of the 665 websites screened, 18 met the criteria. A further 8 sources were found through a targeted search of professional organisations, resulting in 26 sources available for further evaluation. In general, this was found to be low in quality, omitted details recommended by national or international guidance, and was written at a level too advanced for average readers. Conclusion Improvements should be made to the content, quality, and readability of online information so that it both reinforces and complements the discussions between parents and clinicians about testing options during pregnancy.

Since a definitive diagnosis following an unexpected ultrasound finding can inform genetic counselling, pregnancy management, and postnatal care, it is clear that CMA and ES offer a number of potential benefits. There are, however, limitations and unique issues that parents will need to consider when making decisions about testing.
For example, there is the potential for uncertainty in the possible results arising from both CMA and ES. The volume of information extracted may increase the incidence of results that are uncertain or difficult to interpret. 4 Parents may also receive a variant of uncertain significance (VUS) and because, in a prenatal context, phenotypic information is often incomplete, this can make interpretation and subsequent counselling a challenge. 5 Furthermore, variants currently classified as VUS may be reclassified as pathogenic or benign as advances in technology are made. 6 ES and CMA also have the potential to reveal findings which may have wider health implications for family members, and may disclose non-paternity and consanguinity. 7 Taken together, the complexities surrounding the interpretation and subsequent implications of ES and CMA results make the pretest counselling process very important. Clinicians need to discuss with parents all the possible types of results (taking the time to consider the patient's tolerance of uncertainty 8

), manage parents'
expectations about the likelihood of receiving a genetic diagnosis, highlight any limitations with regards to clinical utility, sensitivity and specificity, all the while conveying this information in a way that can be understood. Having to absorb information at a time when they are already anxious and when there are a number of potential outcomes to weigh up (most likely with constraints on clinic time), makes it crucial that parents have access to good quality information about the test to which they can refer outside of the clinic appointment.
Increasingly, the Internet is considered an important source for pregnancy-related information, with research indicating that the majority of pregnant women are likely to search for information online at some point during their pregnancy. [9][10][11] Reasons for searching online include the desire for further knowledge, 12 support in pregnancy decision-making, 13 gaining a sense of control, 14 and seeking reassurance about pregnancy symptoms. 15 Pertinent to the work we describe here, is that parents also cite online informationseeking as a strategy for assuaging feelings of uncertainty surrounding the detection of a foetal anomaly 16 and to find information about prenatal genetic testing. 17 The standard of the pregnancy-related information available on the Internet, however, has been called into question, with research revealing it to be highly variable, 18 of low quality, 19,20 written at a level too advanced for the general population to understand, 21 and lacking in pertinent details. 22 The relative novelty of prenatal genetic tests like CMA and prenatal ES (the latter which has only recently been implemented into mainstream clinical practice), means that we know little about what is available to parents when information about prenatal genetic tests, particularly these new technologies, is sought online. Given the influential role of the Internet in supporting parental decision-making, and the wealth of information that is discussed during pre-test counselling, it is important that online information about prenatal genetic tests is of high quality and written at an appropriate level to allow parents to make informed decisions about and better understand their testing options.
The current study asked two questions: 1) What do parents find when they search the Internet for information about prenatal CMA and ES? 2) What is the content, quality, and readability of the patientdirected online information for CMA and prenatal ES?

| METHOD
The study is formed of two parts to answer each research question.
Firstly, to identify available patient-facing information, we conducted systematic searches using the most popular Internet search engines (Search 1) and then categorised the findings. We also performed a targeted search of websites of relevant professional bodies and organisations (Search 2). To answer research question 2, we then assessed the content, quality, and readability of the information found.

| Design
In this study we have followed the standard process of a systematic review to identify and assess patient information by using a systematic search with defined search terms, clear inclusion and exclusion criteria applied independently by multiple researchers, and an assessment of quality 23 (See PRISMA checklist in the Supplementary Materials). The systematic searches were conducted following the guidance for reviewing health information on the Internet laid out in Eysenbach et al. 24 and Rew et al. 25

| Survey with parents to inform the search strategy
We conducted a brief survey with parents to ensure that our searches mirrored the types of searches used by parents when they look for information about invasive testing online. An invitation and the link to the online survey hosted by SurveyMonkey was posted on the online parent forum of the charity Antenatal Results and Choices (ARC) that supports parents through antenatal testing. Eighteen parents completed the survey: 94% (n = 17) reported searching for information about invasive testing online and 100% said they used Google for online searching. When asked what search terms they would use, 59% (n = 10) said they would search for 'test in pregnancy', 53% (n = 9) for 'antenatal test' and 24% (n = 4) for 'prenatal test '. In an open-text box, respondents added they would search for the name of the specific test offered to them, and/or the gestation at which the test was offered. Sixty-seven per cent of respondents (n = 12) said they would not search for information on social media, and respondents named the website for the National Health Service (NHS; a Government-funded healthcare service for those living in the United Kingdom) and ARC's website as trusted sources of information.

| Ethical approval
As this study is a review of publicly available online information, ethical approval was not required. The survey with ARC parent group members was a consultation to inform the research and is not considered research, as defined by the UK Policy Framework for Health and Social Care Research. As such, it did not require review by an NHS Research Ethics Committee (http://www.hra-decisiontools. org.uk/research/). The survey was conducted with agreement from ARC.

| Search terms
Search terms used to conduct Search 1 were informed by the experience of the research team (which includes a foetal medicine consultant, a genetic counsellor, and a patient advocate) and from responses from the parent survey. We used the following search terms: "exome sequencing"; "genome sequencing"; "microarray" and "array CGH" and paired each one with the following words: "prenatal"; "antenatal"; and "in pregnancy" to create 12 terms in total (e.g., "prenatal exome sequencing", "antenatal exome sequencing", "exome sequencing in pregnancy"). As in Skirton et al., 22 Boolean operators were not included between terms to reflect how parents might likely look for this information (Figure 1).

| Sampling method
Search 1: Each of the 12 search terms was entered into both Google and Bing since research (both our own and by others) has shown that these are the two most popular English-based search engines. 26 We used depersonalised search modes in each search engine, ensuring deletion of cookies between searches. Searches were conducted on the 9th, 10th and 17th November 2020. Each researcher conducted their searches on the same day using the same computer. All searches were completed on the 17th November 2020 and no updates to these searches were performed after this time. We reviewed the first three pages from each search (since research indicates that 75% of users never scroll past the first page of search results 27 ).
Online information is dynamic, and so screen shots of each website eligible for analysis were saved as PDF files. Two researchers independently read through the list of findings, categorising them into broad groups according to the websites' source (e.g., journal article, healthcare organisation), purpose (e.g., academic reporting, patient information), and country of origin. Any website page that appeared more than once (whether across search engines or search terms) was classed as a duplicate hit. All duplicates were removed. Consequently, each website page was only categorised once.

| Identification of patient information describing prenatal CMA and ES
Two researchers (HM, MP) independently assessed the patient information identified in Searches 1 and 2 for inclusion in an assessment of content, quality, and readability.

| Inclusion criteria
Information was included that: a) was directed at patients; b) was in English; PETER ET AL.

| Exclusion criteria
Information was excluded that: a) was directed solely at healthcare professionals; b) pertained only to NIPT for major trisomies, maternal serum screening, ultrasound screening, paternity testing, postnatal testing or prenatal testing in general; c) was in the format of: i) a scientific paper, ii) a news report, or iii) a legal document; d) was duplicated across search engines and, e) appeared on webpages requiring registration or passwords (e.g., academic portals).
Any discrepancies between the researchers were discussed until consensus was reached.

| Measures for assessing the content, quality, and readability of online patient information
Content of online patient information: We checked patient information against suggested pre-testing counselling content from professional guidelines on CMA 28,29 and ES. [30][31][32] This approach is one that has been used elsewhere in the literature. 20,22 The content guide to assess the content of patient information pertaining to CMA comprised 15 items. Each item was rated on a scale from 1 to 5 (where 1 equals "no, the information was not included, 2-4 equals "the information was partially included", and 5 equals "yes, the information was completely included"). The total possible maximum score was 75. Patient information pertaining to ES was rated in the same way, but the content guide comprised 17 items, so the total maximum score was 85. Two researchers (HM, MP) independently F I G U R E 1 Sampling method for Searches 1 and 2 100 - rated all of the eligible patient information. A mean content score for each item and a mean total content score across all sources of information was calculated for each checklist.
Quality of online patient information: The DISCERN Genetics tool 33 was used to assess the quality of the patient information. The DISCERN Genetics tool is a standardised assessment comprising 19 questions, each of which assesses a different quality criterion, plus a final question to which the user should provide a judgement on the information's overall quality. Each item is rated on a scale from 1 to 5 (where 1 equals "no, the quality criterion has not been fulfilled, 2-4 equals "the quality criterion has been partially fulfilled", and 5 equals "yes, the quality criterion has been completely fulfilled").
Three items allow an NA rating (item not applicable) and so the total possible maximum score ranges between 85 and 100. Two researchers (HM, MP) rated all of the eligible patient information. A mean quality score for each item and a mean total quality score across all sources of information was calculated. Shorter sentences with a basic structure receive a higher score than longer, more complicated sentences. Scores higher than 12 are considered too complex for most people. The SMOG calculates a score of readability using the number of sentences and complex words (3 or more syllables) in a piece of text. Higher scores (>14) denote complexity of the material. Scores between 7 and 12 are considered to be the reading level equivalent of 6th graders (UK school age 11-12 years), and is the level at which it has been suggested health information be aimed. 35 Text from each source of patient information was copied into a Microsoft Word document. To maximise accuracy during analysis, any text not in a full sentence (e. g., titles, hyperlinks and bulleted points) was removed, as were references and embedded images. The remaining text from each file was then copied into an online readability programme (https://readabilityformulas.com/). Descriptive statistics for each of the readability tests and correlational analyses to examine the relationship between readability tests was calculated.

Research question 1: What do parents find when they search the Internet for information about prenatal genetic tests, specifically technologies such as CMA and prenatal ES?
Two researchers categorised the findings from Search 1 into broad themes. In line with other studies, [36][37][38] interrater reliability was conducted on 10% of the data (in this case 10% = 26 website hits). Agreement between the researchers was substantial (percentage agreement = 88.5%) and greater than would be expected by chance (Cohen's kappa = 0.87, Z = 9.66, p < 0.05). Descriptive statistics provide information about the characteristics of the website pages identified (Table 1).
Of the 23 sources of patient information that were found through Search 1, five were excluded. This was because the information: referred to NIPT (n = 2), pre-implantation genetic testing (n = 1) or postnatal CMA (n = 1), or was in the form of a media report Analysis of the content of online patient information: Table 3 provides information on the mean content scores by item and the total mean content score across all patient information for each checklist compared with recommended content for patient information on Very few sources, however, mentioned the possibility that CMA or ES may identify consanguinity or non-paternity and none discussed issues of discrimination related to insurance.
Analysis of the quality of online patient information: Scores across both the individual items and the total mean DISCERN Genetics scores showed that the overall quality of patient information was low PETER ET AL.
-101 (Table 4). As with the content of patient information, however, some topics were explained better than others. For instance, the quality of the patient information was high with regards to describing the nature of the test clearly, describing the accuracy of the test results, and providing balanced and unbiased information about the test. In  Explains that there is a possibility that no result will be obtained (e.g., related to sample quality) and a result may not be available before the birth of the foetus in ongoing pregnancies.
3.5 (0.7) 6 Explains that diseases may be identified for which the clinical presentation may vary greatly and range from mild to severe. It may not be possible to predict what the outcome will be in a given patient.

(1.2) 6
Explains that parental samples and additional testing may be needed. Explains that the test may identify consanguinity (a close blood relationship or incest) or nonpaternity Discusses the importance of data sharing in deidentified databases, how genetic material will be stored, and explains who will have access and for what purpose Discusses potential issues related to insurance and discrimination Explains that the test may identify consanguinity (a close blood relationship or incest) or nonpaternity/non-maternity PETER ET AL.
-103 average reader (see Table 5 and Supplementary materials). For instance, text written at the standard reading level should achieve a score of between 60 and 70 on the FRES, and lower than 12 on the GFI. In the current work, however, the mean scores were 46.1 (SD = 8.6) and 15.4 (SD = 2.0), respectively, indicating that the texts are too complex for most. Findings from our analysis using the SMOG also showed that the patient information is written at a standard beyond the 6th grade level (UK school age 11-12 years) at which it is suggested health information be aimed. 35 These results converge with those from our subsequent correlational analyses where strong relationships between the three assessments were found (see Supplementary materials). This confirms that the online patient information identified in our searches requires patients to have literacy skills above the recommended standard.

| DISCUSSION
Receiving unexpected news and being offered genetic testing in pregnancy is likely to be a stressful experience for parents. Parents facing decisions in pregnancy have a great need for information and support around their options. 39 Research has established that genetic literacy among the general public is low, 40 and parents receiving information about prenatal genetic testing at clinical appointments may struggle to absorb everything that is said, especially if they are already distressed. 41,42 We know that patients often search online for information while trying to understand and make decisions about genetic testing and, in the United Kingdom, pregnant women have reported searching in particular for texts written by medical professionals or published by medical institutions. 43 High-quality written  In relation to readability, it is important to note that no readability formula or tool provides a definitive measure of reading level, and that they are not tailored for medical content.
The creators of the DISCERN quality criteria for information on genetic testing point out, for example, that short sentences improve readability scores but patient information is likely to have longer sentences due to the need to define genetic terms within sentences, and this will produce lower readability scores.
They note, however, that embedding definitions within longer sentences is more likely to enhance the actual readability of the text by offering explanation and clarification. 33  -105 anomalies 50,51 and have also been considered an effective tool by parents considering genome sequencing for their children. 52 There are a number of clinical and personal considerations that parents need to weigh up when making the decision to undergo prenatal genetic testing like CMA or ES. Though online patient information should be considered as an addition to, and not a substitute for, clinician counselling (particularly post testing), it remains crucial that it is written at a level that is easy for parents to understand but that does not omit important information. Furthermore, contact details for appropriate information and support services should be included.

| STRENGTHS AND LIMITATIONS
A key strength of the review was the rigorous and systematic approach to identifying and reviewing patient facing-information