The Influence of different Sources on Disease-related Knowledge among Patients with Rare Diseases: A Qualitative Study

Background: Finding reliable information on one of more than 7,000 rare diseases is a major challenge for those affected. Since rare diseases are defined only by the prevalence criterion, a multitude of heterogeneous diseases are included. Common to all, however, are difficulties regarding information access. Even though various quantitative studies have analyzed the use of different information sources about rare diseases, still little is known about how users rate these sources and how their importance changes over time. Methods: Fifty-five patients with a variety of rare diseases and 13 close relatives participated in qualitative interviews. For these interviews, a semi-structured guideline was developed, piloted, and revised. Evaluation followed qualitative content analysis developed by Philipp Mayring. Results: The internet is the most important and widespread information source, especially for early information. Although patients have difficulty dealing with information obtained online, they consider online searching a quick and practical option to gather information. During the course of the disease, personal contact partners, especially self-help associations and specialized doctors, become more important. This is also because information provided online is sometimes insufficiently detailed to answer their information needs, which can be complemented by information from doctors and self-help. Conclusions: People rarely use just one type of source, but rather refer to different sources and informants. The source used depends on the type of information sought as well as other person-related factors such as preexisting knowledge and the disease stage. To improve people’s information searching and connect them with specialists in rare diseases, a central information portal on rare diseases is a suitable access point to provide free and quality assured information for patients, caregivers, and physicians. This would allow not only patients but also doctors to find quality assured information on symptoms and therapies as well as patient associations and specialized


Background
In recent years, rare diseases have become an important issue. Although a uniform definition is still pending, rare diseases are globally characterized only by their low prevalence. In Europe, "rare diseases" is the umbrella term for diseases that affect less than or equal to 1 in 2.000 people. Although rare diseases can differ greatly in type, symptoms, and causes, affected people usually face similar challenges. These include insufficient information. On the one hand, this is because many rare diseases are so rare, that only little information exists. Beyond that, information is often widely dispersed and difficult to find in the vastness of the internet or literature, so that access is limited [1].
However, it is undisputed that information plays an important role in coping with illness [2][3][4]. Understanding an illness's causes, symptoms, and impact seems to be a precondition for dealing with the disease in everyday life and can increase people's quality of life. Moreover, information is an important prerequisite to know where help can be found and pave the way to specialized centers and providers. Both, again, impact patients' health situations. Therefore, knowing how patients as well as their family members, who can also be strongly affected by their relatives' disease, search for information is an important issue. To shape the information gathering process as well as possible and thus meet the patients' information needs optimally, knowledge is needed on how searching is done, what sources are used, and what relevance different sources have.
Moreover, how the use and relevance of different sources change over time should be investigated.
Information searching patterns from patients suffering from chronic but not rare diseases have been extensively analyzed. Numerous studies revealed different sources of information, which are of importance to different groups of patients, but mostly cancer 4 patients [5][6][7][8][9]. These range from physicians, who are often rated as one of the most favored and trusted sources, to information brochures, the internet, as well as nonmedical professionals, such as pharmacists and nurses. Other generally used sources of information include books, newsletters, and mass media sources. For patients with common diseases, family members and friends were also used to gather disease related information. Moreover, some factors have been identified that affect people's search for information. Female patients were reported to inform themselves more often and to use more sources than male patients. Additionally, younger patients and those with a higher education showed more frequent information seeking behavior than older patients and people with a lower educational background. Regarding phase of illness, it was found that shortly after their diagnosis people favored written information while at a later stage relatives and friends become increasingly important.
Because of the specific characteristics of rare diseases, such as unpredictable courses, limited available knowledge, lack of exposure in the media, etc., it can be assumed that information seeking behaviors by people with rare diseases are not completely similar to those of patients with common diseases [10]. However, still little is known about how people affected by a rare disease and their families search for information. Previous studies may be outdated, have relied on few single sources, focused on specific information needs only, and did not focus on rare diseases in general [10][11][12][13][14][15]. A recent study from Teixeira et al. [13] on patients with a rare blood disorder shows that specialists are of particularly great importance when it comes to sources that were widely used for information gathering. In this study, respondents who reported feeling sufficiently informed about genetic testing and its implications for their health mostly reported having received this information from specialists before family doctors and support groups. Even though specialists were also the source they most trusted, they would like to get more 5 information from their family doctor. Furthermore, among patients who did not feel sufficiently informed, the majority answered that they would like to gain information from their family doctor. Additionally, non-medical sources, such as patient associations, websites, nurses, and printed information were of importance to the respondents. After specialists, patient associations were the most trusted information source. Due to the high level of knowledge possessed by patient associations, these are often called patient experts [16].
General practitioners also proved to be one source of information patients would like to receive significantly more information from, according to a study by Matti et al. [12]. They identified preferred sources of information from patients with multiple sclerosis (MS) and found that there was a discrepancy between the amount of information people actually receive and the amount they would like to obtain. Moreover, eye specialists and neurologists were identified as sources they would like to receive more information from.
Regarding MS patient associations and MS specialist nurses, patients reported an almost ideal amount of information that was being provided.
An older study from Lanigan and Layton [11] on patients with a rare skin disorder drew similar conclusions. It also illustrates that specialists were the most used and preferred information source, followed by general practitioners. However, it must be considered that this study occurred before the arrival of the internet, so that its relevance for today's conditions is limited. Wibberly et al. [14] studied patients suffering from a rare lung disorder and identified various information sources. These include primary healthcare physicians, patient information leaflets, as well as the World Wide Web, nurse specialists, and patient support groups. The most valuable information sources were specialists in rare lung diseases, nurse specialists, as well as patient support groups.
Carpenter et al. [10] also confirmed that physicians and the internet were the most used 6 and credible sources for patients with vasculitis to obtain information on medication, followed by pharmacists, and other affected people. Family and friends did not prove to be relevant sources of information, presumably because they do not hold much information on rare diseases. Additionally, gender differences were found. While male patients, unlike female patients, rated their spouses or partners, as well as nurses as fairly credible sources, female patients preferred medication package inserts and the internet as sources of information.
To summarize, family doctors and specialists, the internet, and support groups are of great importance for patients with rare diseases when searching for information on their disease. However, few studies have investigated not only the use, but the perceived credibility and if so, their reasons for it. Since existing studies are based mostly on quantitative methods, further qualitative research is needed to analyze how people with rare diseases assess different sources and on what experiences. Due to its open approach, qualitative research can achieve a deeper understanding of peoples' attitudes and causes.
The aim of this study therefore was to generate a holistic picture of the information sources used, and more specifically, what relevance patients and their families attach to different sources, and if this relevance changes during the course of the disease, and for what reasons.

Methods
Due to the lack of substantial data on information sources in the field of rare diseases, the authors decided on a qualitative study design. Thus, it is possible to explore underresearched areas with maximum openness and reveal all aspects of importance for patients and their families concerning finding information. To detect patients' experiences regarding information acquisition and information sources used, semi-structured interviews were conducted. Therefore, we developed an interview guideline, stimulating 7 people to tell us about their medical history and the way they searched for information (table 1). This was done in close cooperation with an external specialist with long-time expertise in qualitative health research. Individual sources of information and their usefulness could be derived from this. After pretesting the interview guideline with patients with rare diseases, it was revised so it was also suitable for patients diagnosed before or shortly after birth, with no memories of their diagnostic paths. Please tell me about situations in which it was easy to gather information.
Please tell me about situations in which it was difficult to gather information.
Which moments do you consider important in searching for information?
Type of access Please imagine the many possibilities of modern and classic media to comm Please recall your own situation. Which media did you use when search information?
Which medium would you prefer for accessing information?

Completion
Are there any other topics that you would like to talk about?
To select a heterogeneous and balanced sample, several medical experts from the project consortium divided the total of rare diseases into eleven different groups of diseases in accordance with the affected organ systems. It was planned to conduct six interviews in each group as well as ten interviews with patients, who had to wait for at least 10 years until they received a correct diagnosis. Thus, a total sample of 76 patients was planned to be recruited. Nevertheless, upon saturation of interview data, a smaller sample would suffice. Participants were recruited by the Freiburg Center for Rare Diseases (FZSE) at the University Medical Center Freiburg, University of Freiburg, Germany.
The interviews were analyzed following the structured content analysis method by Philipp Mayring [17]. Each audio recording was verbally transcribed and read into MAXQDA analysis software. Subsequently, two researchers worked through the first three interviews and marked all relevant text passages. To develop an extensive system of categories, a deductive-inductive procedure was used. Several categories could be derived from previous research on current information on rare diseases on the Internet. These were completed by inductive categories if they appeared from the text. This procedure was followed by a critical examination and, if necessary, modification of the original categories. Afterwards, the marked text excerpts were analyzed with regard to the research question. Extracted citations were translated by an external translation service, approved by a native speaker and then included in the paper. The following will accompany direct interview quotations: Gender ("M" for male, "F" for female), a consecutive number, age, and status as either a patient ("P") or relative ("R").

Results
Based on the evaluation of the interviews, a multitude of different information sources used by patients and their relatives for gathering information on rare diseases was revealed. The authors disclosed four main themes that were of importance in nearly all interviews. These main themes include the "internet as the first source of information" (theme 1), which describes the relevance of online searches for those affected. The second theme highlights the role of patient organizations and other patients in the information retrieval process, which allow for communication at peer level. Doctors and their perception as a source of information by persons affected is illustrated in theme 3.
Lastly, theme 4 deals with written information.
The internet as the first source of information on rare diseases Many of those interviewed reported in detail about their struggle to receive a correct diagnosis. Often this meant a long-lasting and emotionally charged odyssey. The need for information, once a diagnosis has been made, was accordingly high. In this context, for almost all the respondents, the internet and especially search engines such as Google were one of the first sources to search for information on their own or their relatives' disease. According to the interviewees, this allowed them quick and uncomplicated access to information. In this context, different approaches to how to proceed when searching online for information were identified. Most of the participants simply googled their disease and clicked in a more or less unstructured or unskilled manner through the provided information websites, while others advanced more systematically. In many cases, it was possible to establish a connection between people`s searching approach and their prior knowledge. Patients or family members, who work in the health sector and are familiar with medical terms, demonstrated a more targeted and satisfied approach to research online than those without medical backgrounds. Moreover, people who are familiar with online searches reported fewer difficulties.
"It was when everything was new. We took in all the information we could." (M47, 59 years, P) "Well, the information is primarily shared over the internet." (F14, 57 years, P) Medical databases on the internet, such as PubMed, were hardly used. Often only interviewees with medical backgrounds reported knowing these sources of information.

"(…) I enter it into the internet and then find the information. It
This was described as an advantage in relation to other patients who do not have medical backgrounds, due to its high quality and current information.  Of particular importance is also the fact that patients and their families normally have fixed individual contacts in the centers for rare diseases, who are entirely familiar with their disease history and symptoms. In this context, people also positively highlighted not needing to repeatedly explain their condition, which was felt as a relief. Some people also discussed longstanding and trusting physician-patient relationships arising from that.
From the interviews, it became clear that patients and their families also see specialists and centers for rare diseases as a (good) complement to the range of information offered from their patient's association. While those hold relevant and most trusted information on most issues beside medical issues, specialists are especially important regarding detailed aspects concerning therapy, diagnosis, etc.
Printed information -high quality, but not up to date information and sparsely used Even though many of the patients and their relatives in our interview sample received information to a large extent from the internet or personal contacts, others, however, reported the wish for printed information. On the one hand, this is because people appreciated the possibility of holding something in their hands, where they can look things up again, when they feel like it. This was especially emphasized at earlier stages of disease progression.
"(…) I would rather need it in writing, to refer back to again." (F31, 36 years, P) Shortly after diagnosis, for example, information brochures are perceived as helpful sources, since they provide comprehensive and often comprehensible information.
Moreover, people reported that brochures are well suited for bringing them on the day of doctors' appointments to give them a review of their disease. At later stages, however, brochures do not cover people's needs for more specific and detailed information. Some of the interviewees found it helpful to read magazines offered by patients' associations. Additionally, for those who did not actively participate in regional meetings or did not look for personal exchange, this type of information provision was important. In this connection, patients especially highlighted experience reports from other affected patients and families as valuable information.
"The most important source of information was simply/ the newspaper of Glandula. Additionally, specialist books were used for information gathering, but some of the interviewees put them aside, discouraged by the medical terminology. Especially in the time shortly after diagnosis, they exceeded the capabilities of patients and relatives.
People also complained that books would often not be up to date, a fact that can be important when considering that specialist books often refer to medical issues such as therapeutic options, which could be subject to frequent amendment.

"(…) and that is anyway the medical terminology and how can you as a layman go and
change it for yourself, or read it, it will not do, it does not work." (F17, 47 years, P) "As mentioned before, books, they definitely are not; they definitely do not have the play an important role when gathering information [11][12][13][14]. However, to date, it has been unclear what experiences patients with a rare disease and their families have had when they have used these types of sources, how they assess them, and how their value changes over time. We were also able to show that the use of different sources is not stable, but can change over time. While, for example, people regarded the internet as an uncertain source of information due to information overload in the beginning, at a later stage their perception changed as they learned a more targeted approach to search and carefully choose which websites to use. Thus, our results indicate that the importance of different sources varies depending on, among other things, the state of disease progression and the state of knowledge.
Great potential for patient associations Although possibilities for participation have increased over the past decade, in the future self-help associations should be even more integrated to improve patients' health care. As we have shown, no patient or relative from our interview study was made aware of the possibility of contacting a patient organization by their doctor. Under the term of "selfhelp friendliness" different attempts to institutionalize relationships between carers from the in-and outpatient sector and self-help associations in Germany have been made [19].
In this context, a set of commitments has been agreed to sustainably integrate self-help on a collective level into health services [20]. In the stationary sector, for example, different quality criteria have been defined to ensure a close connection between hospitals and self-help. So far, however, few care facilities have joined these voluntary collaborations. In the future, carers in the field of rare diseases should also endeavor to collaborate with patient associations. Besides opening their medical care provision to 22 knowledge and experiences from patient organizations, they could also strengthen contacts between their patients and self-help groups and thereby support their patients' coping processes.
However, to permanently secure patient organizations' work, sufficient funding is required. Even though, the funds approved by statutory health insurance recently increased due to the Prevention Act (PrävG) adopted in 2015 [21], it is still unknown whether patient organizations have sufficient financial resources to sustain their important work. Especially, for self-help in the field of rare diseases, which is often characterized by local groups with a limited number of members and low public visibility, sustainable funding to maintain their services seems to be endangered; hence, further research is needed. Moreover, still little is known about the economic potential of selfhelp groups. The study shows that patient organizations play a major role for patients to find highly specialized care units. This is also interesting from an economic point of view.
Patient organizations do not only provide information very efficiently at low cost but also provide a communication platform for patients to exchange their worries, fears, experiences, and observations. Until now, the role of patient organizations has not been assessed from a health economic point of view and, therefore, should be studied in the future.
Central information portal on rare diseases as a contact point for patients, their families, and doctors Besides the great potential for self-help associations, it has been demonstrated that online information is currently of crucial importance for patients and their families to gather information. It especially enables newly-diagnosed patients to search for information quickly and easily. Additionally, in more advanced stages of the disease, people rely on online information in case they need information on current developments.
Dissatisfaction, however, arose due to the unfiltered flood as well as the unknown quality of the information. Therefore, new approaches for optimizing and developing user oriented information systems are necessary. For this reason, initial efforts have been made to establish and implement an information portal on rare diseases (ZIPSE) [22], where patients, their relatives, as well as medical professionals can access clearly presented and high-quality information from a central web based point. Since information provides the basis for coping with the disease and receiving specialized care, such a portal can help to improve patients' health situation sustainably. Besides increasing their quality of life, reduced doctor-hopping and targeted therapy can help to use limited financial resources more adequately. This also allows doctors, who cannot hold information on all 7,000 rare diseases, to obtain information, for example, on treatment options, medication, or specialized medical colleagues when necessary. This could also help on the caregivers' part to make their patients' healthcare more efficient and compensate for the uneven level of information, which was often criticized in the interviews. Physicians should be conscious of their important role in people's health care and endeavor to better inform themselves on their patients' diseases, and give them specific assistance regarding which websites to use and where self-help contact partners can be found.

Limitations
The purpose of this study was to gain insights into how people affected by rare diseases experienced their search for information, which sources of information they used, and how they assess different sources. Unfortunately, not all aspects that have been mentioned in the interviews could be reproduced in detail in this manuscript due to lack of space.
Rather, the main themes were presented as comprehensively as possible. Therefore, supplementary observations regarding information sources and their potentials should be a topic for further publications.
Due to the qualitative approach of this interview study, it is not possible to generalize the findings to patients with rare diseases and their relatives as a population. It must be kept in mind that findings from a qualitative survey must be embedded in their spatial and temporal context [17]. However, that does not mean that they are not transferable to other people and situations. The creation context, however, must be considered when applying the findings to a new context.

Conclusions
In our study, various information sources, such as the internet, self-help organizations, and doctors, have been confirmed as important access channels for people living with a rare disease and their families. Due to the qualitative approach, reliable statements on the reasons why, and how important they are to patients and their families have been made for the first time. Moreover, it was possible to show how the importance of different sources changes over time.
For physicians, especially those who do not deal with rare diseases daily, this does not mean they must hold information on all 7,000 rare diseases, but they do need to know where to get quality assured information when necessary. For them as well as patients and their families, a central information portal, such as ZIPSE, might be an option.
contributed to the methodological conception of the interview study. AB and DR conducted interviews and contributed to the interpretation of the results. FZ recruited patients and relatives for participating in our study. SL drafted the manuscript and all authors were involved in its review and revision. All authors read and approved the final manuscript.