BMJ Open...For peer review only Leukaemia early diagnosis protocol version 3, Apr 24, 2009 Our study...

For peer review only

“Shouting from the roof tops”: a qualitative study of how children with leukaemia are diagnosed in primary care

Journal: BMJ Open

Manuscript ID: bmjopen-2013-004640

Article Type: Research

Date Submitted by the Author: 08-Dec-2013

Complete List of Authors: Clarke, Rachel; John Radcliffe Hospital, Acute General Medicine Jones, Caroline; University of Oxford, Primary Care Health Sciences Mitchell, Christopher; John Radcliffe Hospital, Department of Paediatric Oncology/Haematology Thompson, Matthew; University of Oxford, Department of Primary Care Health Sciences

<b>Primary Subject Heading</b>:

Diagnostics

Secondary Subject Heading: Paediatrics, Haematology (incl blood transfusion), Qualitative research

Keywords: Leukaemia < HAEMATOLOGY, Leukaemia < ONCOLOGY, Paediatric oncology < ONCOLOGY, Paediatric oncology < PAEDIATRICS, QUALITATIVE RESEARCH

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

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TITLE PAGE

“Shouting from the roof tops”: a qualitative study of how children with leukaemia are diagnosed in

primary care

Rachel T Clarke, Caroline H D Jones, Christopher D Mitchell, Matthew Thompson

Rachel Clarke, Core Medical Trainee (ST1), Oxford University Hospitals NHS Trust, John Radcliffe

Hospital, Oxford, OX3 9DU

Jones, Caroline H D

Senior Researcher, Department of Primary Care Health Sciences, University of Oxford, Radcliffe

Observatory Quarter, Woodstock Road, Oxford, OX2 6GG

Mitchell, Christopher D

Consultant Paediatric Oncologist/Haematologist, Department of Paediatric Oncology/Haematology,

Children’s Hospital, John Radcliffe, Oxford, OX3 9DU

Thompson, Matthew J

Reader in Primary Care, Department of Primary Care Health Sciences, University of Oxford, Radcliffe


Correspondence to: M. Thompson, [email protected]

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“Shouting from the roof tops”: qualitative study of how children with

leukaemia are diagnosed in primary care

Rachel T Clarke1, Caroline H D Jones

1, Chris Mitchell

2, Matthew J Thompson

1

Abstract

Objectives

To investigate the pre-hospital presentation of paediatric leukaemia and identify the disease and non-

disease related factors which facilitate or impede diagnosis.

Design

Thematic analysis of qualitative semi-structured interviews.

Setting

One tertiary referral centre in Southern England.

Participants

21 parents and 9 general practitioners (GPs) of 18 children (<18 years old) with a new diagnosis of acute

leukaemia.

Results

The majority of children were first seen by GPs before the characteristic signs and symptoms of

leukaemia had developed. In their absence, behavioural cues such as the child becoming apathetic or

‘not themselves’ often triggered parents to seek medical help. Most GPs were unclear about the nature

and severity of the child’s presentation: then, safety netting, thorough history-taking and examination,

and reliance on contextual information about the parents or from prior hospital paediatrics experience

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were used to manage diagnostic uncertainty. The nature of the doctor-parent relationship both helped

and hindered the diagnostic pathway. GPs’ prior perceptions of parents as being ‘sensible’ or ‘worriers’

influenced how gravely they treated parental concerns, with ‘worriers’ being taken less seriously. Some

parents believed GPs failed to listen to their anxieties and discounted their expert knowledge of their

child. Specific delay factors included lack of continuity of GP; some GPs’ reluctance to take blood from

children; and some parents feeling unable to voice effectively their concerns.

Conclusions

The presentation of paediatric leukaemia in primary care differs from that described in many hospital

studies, with greater diversity and intermittency of symptoms, and the frequent absence of ‘red flags’ of

serious illness. A wide range of non-disease related factors potentially delay the diagnosis of paediatric

leukaemia, including tensions in the doctor-patient relationship and doctors’ cognitive biases. The

identification and attempted modification of these factors may minimise diagnostic delay more

successfully than raising awareness of ‘red flags’ of disease.

Article summary: strengths and limitations of this study

• This is the first study, to our knowledge, to explore factors in the pre-hospital diagnosis of a

serious childhood illness (paediatric leukaemia) from the perspectives not only of parents but also

GPs.

• It provides an original perspective on the challenges inherent in diagnosing rare illnesses,

identifying a wide range of non-disease related factors potentially delaying the diagnosis of

paediatric leukaemia, including tensions in the doctor-patient relationship, doctors’ cognitive

errors, and systems factors such as discontinuity of care.

• It also reveals that the presentation of paediatric leukaemia in primary care differs from that

described in many hospital studies, with greater diversity and intermittency of symptoms,

greater prominence of behavioural changes, and the frequent absence of ‘red flags’ of serious

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illness.

• The study is potentially limited by the recruitment rate for GPs, with approximately half choosing

not to take part, and the fact that the data were gathered from a single tertiary centre whose

catchment area may not be representative of practice nationally.

• The inclusion of control children without leukaemia could also have strengthened our analysis.

Introduction

Accurate discrimination between presentations of rare, life-threatening disease and those of common,

self-limiting illness is one of the defining challenges of general medicine.1 Paediatric cancer is perhaps

the archetypal disease ‘not to miss’. In developed countries, cancer now causes more childhood deaths

than any other serious illness, including meningitis, yet a general practitioner (GP) will encounter a child

with cancer only once every 20 years, and a quarter of children wait more than 3 months to obtain a

diagnosis.2

3 Failure to spot a childhood malignancy can lead to adverse outcomes including avoidable

deaths, while over-cautiousness may generate unnecessary investigations and referrals.

Improving the early diagnosis of childhood cancer is a key priority for many health services. The UK’s NHS

Cancer Plan, for example, stipulates that all patients, including children, with “red flag” features of

possible cancer, should be seen by a specialist within 2 weeks of referral by their GP.4 However, the vast

majority of children with cancer are not diagnosed by this pathway, but are identified by other routes,

such as direct presentations to emergency departments.5 Relying on identification of red flag features to

prompt suspicion of a serious illness may be flawed if the red flags occur only late in the evolution of an

illness, lack sufficiently discriminatory value, or are not applied in practice. In addition, for low

prevalence diseases (such as childhood cancer in primary care), even clinical features with high positive

likelihood ratios only increase post-test probability by a small amount. Furthermore, the red flag

approach may be too simplistic, focusing only on the disease-related determinants of diagnostic delay.6

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The reality of the diagnostic process is a series of interactions over time between clinicians, patients and,

in paediatrics, their parents/carers. Therefore, a wide range of non-disease-related factors such as the

nature of the doctor-patient relationship, continuity of care or a doctor’s cognitive biases, may equally

impede the diagnostic process.

We aimed to explore the period leading to diagnosis of paediatric cancer, in order to identify the disease

and non-disease related factors which facilitate or impede diagnosis. We conducted narrative interviews

with parents and GPs of children presenting with a new diagnosis of leukaemia. Leukaemia is the most

common malignancy of childhood, with an annual incidence of nearly 4000 cases in the United States

and 450 cases in the UK, and is responsible for a third of child cancer deaths.7 Leukaemia represents a

major diagnostic challenge for primary care clinicians as the disease symptomatology is diverse, affects

all body systems, and mimics common childhood illnesses. " Moreover, the time from symptom onset to

diagnosis ranges from one day to several months, but is typically several weeks, suggesting considerable

scope for improvement in speed of diagnosis.8

Methods

Design

We used a qualitative study design so that participants could describe the whole diagnostic process in

their own terms, and potentially raise issues not anticipated by the researchers.

Sample

Parents of all children (<18 years) admitted to one tertiary referral centre in Southern England between

July 2009 and July 2012 for treatment of newly-diagnosed leukaemia were eligible for inclusion. GPs who

had seen the child during the period from symptom onset to diagnosis became eligible once the parent

had agreed to participate. Parents were initially approached in person by the child’s consultant or nurse

specialist (the clinical team used their discretion to not invite parents for whom they felt the study was

inappropriate). If parents agreed to consider participation, a researcher (RC, a female doctor) met them

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in person on the paediatric oncology ward to discuss the project and supply a patient information sheet.

RC emphasised that she was not involved in the child’s treatment and that the care the child received

would not be affected in any way by the decision to participate or not; she also emphasised that the

interview would be confidential. During a subsequent telephone call or face-to-face meeting with RC, a

minimum of 48 hours later, verbal consent for participation was obtained from parents and a date for

the interview was arranged. Written consent was obtained immediately before each interview was

recorded. GPs were contacted by letter and a follow up telephone call to be informed of the study and

invited to participate. Those who agreed gave verbal consent by phone and written consent immediately

before each interview was recorded. Recruitment stopped once saturation was reached (i.e. new

interviews no longer elicited new themes).

Data collection

All interviews were conducted by one researcher (RC). Parent interviews took place in a private room at

the hospital or in parents’ homes, according to their preference, and GPs were interviewed in their

consulting rooms. Interviews, which took place within 3 months of diagnosis, lasted around an hour,

ranging in length from 15 minutes to 2 hours. GPs were offered reimbursement for their time, though 7

of the 9 GPs interviewed declined this.

Interviews were semi-structured, using a topic guide to which additional questions were added as new

themes emerged. The topic guides and prompt lists were informed by issues identified in the literature

pertaining to diagnostic delay in general, with an emphasis on childhood cancer. Parent and GP topic

guides were non-identical, though the topics overlapped to some degree. Parents were asked to tell the

whole story of their child’s illness, from when they first noticed something was not right, through to

diagnosis. GPs were asked to describe their consultation(s) with the child, their clinical reasoning and

actions; and their views of any factors which may have influenced the diagnostic pathway. New topics

were added iteratively as they emerged during interviews, for example, parental use of the internet to

diagnose leukaemia. Interviews were digitally recorded and transcribed verbatim. The accuracy of

interview data was cross-referenced against the presentation as described in the child’s electronic

primary care record and hospital paper records.

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Data analysis

Data were analysed thematically according to the grounded theory approach. Analysis and interviewing

proceeded concurrently, with two researchers (RC and CJ, a non-clinical researcher) independently

reviewing all transcripts and identifying categories and themes. Together they developed a systematic

coding frame, and RC used this to assign segments of transcripts to coding categories. The coding frame

was edited as analysis and data collection proceeded. Parent and GP interviews were analysed

simultaneously using similar coding frames, with the analysis of each informing the other. All authors

discussed the most salient themes regularly, starting after the first few interviews, to refine and develop

the coding frame. All research team members discussed any differences in interpretation, until

consensus was reached.

Results

We interviewed 18 mothers, 3 fathers and 9 GPs of 18 children with leukaemia. Children’s characteristics

are summarised in Table 1. Given the low prevalence of paediatric leukaemia, and hence the increased

risk of patients being inadvertently identifiable, we have presented only a limited selection of

characteristics to maintain anonymity. Furthermore, in order to preserve patient, parent and doctor

confidentiality, we have assigned patients individual identification codes (numbered 1 – 18) which are

entirely unrelated to the GP identification codes (letters A – I). All parents approached agreed to

participate, and 9 of the 18 eligible GPs agreed. Three parents were not approached because their

clinical team did not feel it was appropriate. When parental and GP verbal accounts were cross-

referenced against hospital and GP records, no major discrepancies were found (but parent accounts

were much more detailed). We present the results under categories reflecting the main steps in the

diagnostic pathway, namely presentation of leukaemia, parents’ interpretation of symptoms, doctors’

appraisal of children, and parent-doctor interactions. The main sub-themes to arise during analysis are

presented within these categories. Figure 1 summarises all those sub-themes to emerge as factors

potentially impeding the diagnosis of paediatric leukaemia.

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1. Presentation of leukaemia

The presenting features of leukaemia described by parents were diverse, intermittent and non-specific,

covering a broad range of behavioural and physical changes (Table 2). Typically, the symptomatology

evolved over weeks to months, with non-specific early features such as fever, pallor and fatigue

mimicking those of common, self-limiting, minor illnesses. More specific features, such as a non-

blanching rash, usually appeared later in the illness trajectory, though in a small minority of children they

heralded its onset. Altered behaviour was often parents’ first cue that something was seriously wrong:

“On Tuesday last week he kept crying for a scooter and I said okay, let’s go to Toys R Us,

I’ll buy a scooter for you… We came home, I cobbled it together, he said he wasn’t

playing and I [asked], ‘what’s wrong?’ He said, ‘I don’t want to play.’ I touched his body. I

noticed it was a little hot and I said, ‘now this is very unusual… No matter how sick he

was, [he] would get up and play with a new toy.” (Mother of child 2)

The emergence of unusual and alarming signs such as a “meningitis-type rash” (mother of child 5) was

infrequent.

2. Parents’ interpretations of symptoms

Most parents initially attributed their child’s symptoms to minor, viral illnesses, or to other ‘innocent’

explanations such as ascribing joint pains to sporting activities, refusal to walk to attention-seeking, and

bleeding gums to poor dental hygiene:

“He’s a 12 year old boy who plays a lot of sport, and he’s probably going to get growing

pains. And, OK, the bruises, well, he’s playing rugby, what do you expect?” (Mother of

child 11)

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Some parents believed initially that since their child was behaving normally, their physical symptoms

must not be serious. Most parents had minimal or no prior knowledge of leukaemia, but imagined it to

be incompatible with normal behaviour. Altered behaviour (as above) often triggered parents’ first

serious concerns (and consultations), as did the persistence or worsening of initially innocuous physical

symptoms, such as fevers or bruises.

3. Doctors’ assessment of children

GPs, like parents, commonly considered initial presentations to be consistent with mild, self-limiting

illnesses such as viral infections, a pulled muscle or growing pains. A smaller number of doctors were

certain that the child before them was severely unwell, given their physical appearance and behaviour,

and the gut instincts those provoked:

“This was one of those ones where I opened the door and thought, ‘I ought to telephone,

to get the hospital on the line, yeah.’… I just remember that lurch of your stomach, you

know, when you think ‘oh’… She wasn’t bouncy, she was very quiet, she seemed to be in

pain actually, she was moaning, and she looked slightly swollen, her face was rounder

than it should have been.” (GP I)

The absence of a specific diagnosis in these cases did not deter GPs from making an urgent hospital

referral. Indeed, some explicitly identified their most important role as being that of discriminating

between seriously unwell and essentially healthy children, rather than making a specific diagnosis of

leukaemia or any other illness:

“I didn’t have differential… No, my differential diagnosis was at that point not

important... Leave that to the hospital. He needed to go in there and then, whatever the

diagnosis turned out to be.” (GP D)

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A few GPs suspected leukaemia, but only one was certain of this diagnosis, based on the patients’ red

flags of chronic fevers, pallor and unexplained bruising.

When GPs were unsure about the nature and severity of the child’s illness, they deployed a range of

strategies to manage their uncertainty. Some gave explicit ‘safety netting’ advice, about when to return

for further consultation, for instance, should the child’s symptoms not resolve. Others sought to

eliminate the most serious, albeit uncommon, potential causes of the child’s presentation:

“He did look pale and tired and unwell, but as you know there are many reasons for that,

but his mum was very keen on getting a blood test… I do remember thinking, yes,

leukaemia is the reason I want to do a blood test, because that’s the one thing I wanted

to exclude” (GP F)

Some GPs drew on contextual information such as their prior perceptions of parents as ’sensible’ or

‘worriers’, though several GPs acknowledged this strategy could backfire if the legitimate concerns of

‘worriers’ were not taken seriously. Attempts to refine the differential on the basis of children’s social

and cultural context could also have a negative impact, as in the case of a girl of ethnic minority origin,

who presented with recurrent bone pain, fevers and weight loss. When a blood test showed a microcytic

anaemia, her GP prescribed supplements for iron and vitamin D deficiency, presuming that, like other

girls of her ethnicity, she had a restricted diet and limited exposure to sunlight. He later reflected that

the cultural context: “may have produced a fog in our brains…. I’d gone off on this vitamin D deficiency

and malnutrition concept in my head, and wasn’t breaking out of that, but the picture of the

presentation just wasn’t fitting” (GP E).

When one child’s presentation and recent consultation record were difficult to interpret clearly, the GP

managed uncertainty by asking the parent to re-tell the whole story from the beginning, leading to the

suspicion of leukaemia:

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“If somebody tells me something and it just doesn’t match what’s on the computer, then

I would prefer to make my own judgement and so I prefer to hear the patient’s story

from themselves. Sometimes… if they go back to the beginning they’ll remember

something that suddenly is a bit more meaningful that they didn’t think of two weeks

ago to tell you.” (GP A)

GPs commonly cited the importance of training and prior experience in shaping their differential. Some

considered duration of clinical experience per se to be key, while others regarded specific experience of

hospital paediatrics, and particularly managing acutely unwell inpatients, as being more important,

particularly in developing a gut feeling or intuition for spotting unwell children.

Some parents expressed surprise that the GP did not physically examine their child, as in child 10, who

presented with severe abdominal pain the morning after a vomiting bout:

“The cold went away but the pulled muscle of the tummy ache didn’t go away. So we

went to the GP who didn’t really examine him, I have to say, just sort of looked at him

and said, ‘he’s got a pulled muscle, it will go away. If it doesn’t go away, come and see us

in a week.’ ” (Mother of child 10)

Some GPs also acknowledged reluctance to palpate young children’s abdomens, for a number of reasons

including the difficulties of so doing within a 10 minute consultation.

4. Parent-doctor interaction

Most doctors explicitly assessed both the parent and their child during consultations, with the degree of

parental concern influencing some GPs’ own level of anxiety. Several GPs, particularly those with

additional training in paediatrics, underlined the importance of a parent stating that their child was ‘not

right’:

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“As paediatricians you know from the word go, it’s drummed into you, that if a parent

says, ‘she’s not right’, if you’re thinking of sending a child home and she’s still saying

‘they’re not right’, you admit them. You always listen because the parent’s intuition is

right and you’ve got to find out why they’re feeling that way.” (GP A)

Changes in parents’ typical consultation behaviours, for example presenting with greater frequency,

were also perceived as concerning. One GP arranged an unscheduled, emergency appointment after the

child’s mother uncharacteristically approached her in a public setting: “my alarm bells were completely

ringing…she’d never normally do that, she’d normally leave a message or something, so that was unusual

and made me think that she must be very worried” (GP I).

GPs placed greater importance on parental concerns in parents they perceived to be “sensible”

compared to those they judged as “neurotic” or “worriers” (see above). For example, one mother

explicitly told her GP that she believed her child had leukaemia after searching for information about this

disease herself, and consequently asked for a blood test. The GP advised against doing so, in part since

the child seemed well on examination, but also because the mother had been excessively anxious in the

past about minor symptoms:

“Maybe my brake on doing a blood test was that I felt she was worried unnecessarily,

because I’d seen her quite a lot, lots of phone calls about little things like a rash and a dot

and a scratchy area and lots of things that, you know, always seemingly caused a lot of

alarm, that weren’t a problem… It is a case of… the seemingly sensible Mum versus the

Mum who is, maybe you should or you shouldn’t stereotype, just being particularly

anxious, and yes, it does make a difference as to what they’re telling you and the

emphasis on it.” (GP G)

Just as parental concern influenced GP concern, so too were some parents guided by their GP’s degree of

anxiety:

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“I’m so naïve. If a GP is saying to me ‘she’s well in herself, I really don’t think it’s serious,’

then… in the future the first thing that I think to myself is, ‘the GP was fairly confident

that it was nothing to worry about, so I’m not going to worry about it.’” (Mother of child

15)

Indeed, several parents described using their GP’s innocent interpretation of their child’s symptoms to

allay their deeper, unvoiced instincts that something more serious was wrong:

“You don’t want your child to be sick, terribly ill, you just want someone to say ‘it’s fine, it’s alright’ so

we kind of clung onto that, I suppose” (mother of child 10).

Some parents believed their GP dismissed, rather than listened to their concerns, yet felt unable to voice

this. Over a 4 month period, one young girl had multiple GP contacts, for recurrent infections, fever,

weight loss and pallor, while her mother became increasingly distressed: “I always feel very intimidated

by male doctors in particular because I always feel that, you know, I haven’t got half a brain that they’ve

got… [I was] made to feel as though, yes, you might have given birth to this thing, but you don’t know

anything about this thing… I almost wanted to scream at him, ‘look there is something wrong with my

child!’” (mother of child 1).

Several GPs acknowledged that they may have failed to heed parents’ concerns sufficiently:

“She did feel like she was shouting from the roof tops that there was something not right

and no one was listening… Seemingly she was shouting but maybe not saying the words

that we could hear.” (GP G)

Upon feeling that their GP failed to take their concerns seriously, some parents circumvented the GP’s

traditional gatekeeper role to hospital services, for instance by calling the emergency services or taking

their child to an emergency department. Other parents played a direct role in obtaining their child’s

diagnosis by researching their symptoms on the internet and diagnosing leukaemia themselves. Several

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consequently asked their GP directly for a blood test, as described above, with some GPs agreeing, and

others disagreeing to do so. Time constraints during 10 minute primary care consultations were

highlighted as a barrier to taking blood from a young child, as were fear of traumatising children, lack of

experience, and a general ethos in general practice of not taking blood from children:

“There is very much that statement, “oh, we don’t want to put him through it”, and I’ve

adopted that statement, and I never used to say it because of having done paediatrics.

I’ve taken so much blood from so many little ones, and you can do it in a nice way and…

with a bit of skill make it pretty much a non-event, and so I didn’t actually have that spin

on it too much, I’ve adopted this from my general practice training.” (GP G)

Lack of continuity of GP between consultations was cited by parents and GPs alike as contributing to

diagnostic delay. Several parents also identified the problem of reception staff denying access to doctors,

such as one father who was forced to describe the crippling nature of his daughter’s pain “to a

receptionist, because you can’t speak to the GP unless you have an appointment with the GP. I said

again, ‘look this is the problem, talk to the GP’ and they wouldn’t even transfer me to the GP” (father of

child 8).

Discussion

Main findings

A wide range of interacting disease and non-disease related factors affected the speed and accuracy of

diagnosis of leukaemia in children prior to hospital admission. The main themes to emerge from this

study are firstly that the majority of children were seen initially by GPs before the characteristic clinical

features of leukaemia had developed. In their absence, behavioural cues, such as the child becoming

apathetic or ‘clingy,’ featured prominently in triggering parents to seek help. When a child did present as

acutely unwell, GPs recognised this swiftly, drawing primarily on their physical appearance and

behaviour, and the gut feelings these provoked. A second major theme, applicable both to parents and

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GPs, was the misattribution of presenting signs and symptoms to common, self-limiting illnesses or other

‘innocent’ explanations. In part, this reflects the non-specific and diverse nature of the early presenting

features. The third main theme relates to what GPs do when unsure what is wrong with the child.

Strategies to manage diagnostic uncertainty included 'going right back to the beginning' when the clinical

course is vague; having a good safety netting system in place; seeking to eliminate the most serious

potential causes of the presentation; and drawing on their prior contextual knowledge of the parent and

their prior experience and training in paediatrics. Fourthly, the doctor-patient relationship had a

significant impact on helping and hindering the process of obtaining a diagnosis. For example, sometimes

GPs’ concerns, and hence actions, were shaped by how anxious they judged the parent to be, yet some

parents also found the doctor’s level of anxiety assuaged or exacerbated their own. A GP’s prior view of

a parent as being ‘sensible’ or a ‘worrier’ could influence how gravely they treated their concerns, with

‘worriers’ being taken less seriously. While some GPs stressed the importance of listening to parents,

many parents believed GPs failed to take their anxieties seriously, with these concerns not always being

voiced. A fifth major theme was the influence of systems factors on the diagnostic pathway. For

example, both parents and GPs identified lack of continuity of care between GP visits as being

detrimental. Some parents also raised the problem of non-medically trained reception staff determining

access to urgent appointments. Finally, the constraints of short appointments were raised by some GPs

as potentially discouraging them from two diagnostically useful activities: taking blood and palpating

abdomens.

It is possible to classify some of the key findings above in terms of whether they are disease or non-

disease related factors impeding diagnosis (figure 1). We believe this is a valuable conceptual framework

for thinking about rare illnesses, since it highlights the full range of factors potentially influencing speed

to diagnosis, rather than the presenting features of the illness alone.

Strengths and weaknesses

This is the first study to explore factors in the pre-hospital diagnosis of paediatric leukaemia from the

perspectives not only of parents but also GPs. In-depth narrative interviews are ideally suited to

investigating a behavioural process such as diagnosis, since they allow participants to articulate fully their

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own account of events, enabling a rich understanding of why individuals behaved as they did at each

stage. Being drawn from a tertiary referral centre covering a large geographical area, our sample was

diverse, and included fathers as well as mothers, parents from various socioeconomic and ethnic

backgrounds, and GPs with various levels of experience. Data were analysed by a doctor and a non-

clinical researcher: their different prior knowledge, assumptions and perspectives strengthened the

analysis.

The study had several limitations. First, we recruited a limited number of GPs, with approximately half

choosing not to take part. We were not able to ascertain specific reasons for this, but some GPs may

have been dissuaded from participating by fears of judgement or medical litigation mentioned in the

consent forms they had to sign, or due to time constraints. Second, there was an unavoidable risk of

recall bias, but this was minimised by interviewing participants as soon as possible after diagnosis.

Finally, the inclusion of control children without leukaemia could have strengthened our analysis.

Comparison with existing literature

Most descriptions of how childhood leukaemia presents are based on small cohorts of hospital patients,

describing a relatively short and defined list of signs such as pallor, fever and unusual bruising.9-12

In

contrast, our study highlights the importance of wide-ranging behavioural changes and clinical features

in heralding illness onset and triggering consultations in primary care. Previous qualitative studies of

childhood meningococcal disease have analysed doctors’ diagnostic reasoning, and several qualitative

studies have explored parents’ experiences of a cancer diagnosis in their child.13, 14

No studies, to our

knowledge, have sought to combine simultaneously analysis of parental and clinician perspectives. The

small but growing literature on diagnostic error tends to view ‘doctor delay’ exclusively from the doctor’s

perspective, with the implicit assumption that it is predominantly what the doctor does or does not do

that shapes this component of the symptom interval.15, 16

However, our data demonstrate the pro-active

role many parents play in obtaining their child’s diagnosis, for example, through refusing to accept their

doctor’s decisions, bypassing the GP’s role as gatekeeper to secondary care, using the internet to make a

diagnosis of leukaemia themselves, or asking for a blood test. Our findings demonstrate clearly how

doctors’ cognitive errors can potentially delay diagnosis in primary care. For example, some GPs decided

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early in the illness process that they knew the underlying cause of the child’s symptoms (a minor illness)

and therefore did not actively seek alternative diagnoses – so-called ‘premature closure’.16

Implications for practice and research

Our findings suggest that ‘red flag’ based algorithms for aiding diagnosis of paediatric cancers such as

leukaemia may be of limited value, given its frequently non-specific and fluctuating early features. Our

results concur with those of a recent case control study of primary care records in the UK, which found

that the alert signs identified in NICE guidance for childhood cancer were recorded more commonly in

cases than controls, yet that only a quarter of cases had any alert symptoms recorded in the three

months prior to diagnosis.4, 6

Instead, clinicians should be sensitive to the fact that non-disease related

factors such as errors in doctors’ cognitive reasoning, tensions in the doctor-parent relationship, and

systems factors such as lack of continuity of care are all potentially drivers of diagnostic delay. Specific

practical implications might include GPs having a lower threshold for taking blood in children, examining

young children’s abdomens more readily, and introducing a system whereby any children presenting

frequently, or more frequently than usual, trigger more detailed scrutiny by clinicians. More generally,

current GP training, in which only 40% of trainees experience a hospital paediatrics placement, should be

reformed so that all GP trainees have core paediatric training.17

On-going professional development

should build skills and confidence in examining and taking blood from young children.

While the importance of good doctor-patient communication is nothing new, our findings underscore its

unique significance for diagnosing rare childhood illnesses in general practice. In the absence of hard

clinical signs of disease, when the patient is too young to express themselves verbally, and when parents

have exclusive insight into their child’s well-being based on their years of parenting, a doctor’s abilities to

communicate well with the parent are paramount. ‘Listening to the parent’ is something of a mantra in

paediatrics; our findings highlight in addition the importance of what is unsaid between parent and

clinician in shaping the diagnostic pathway. First, some doctors and parents silently take their cue from

each other as to how anxious they should be themselves, with the concomitant risk of false reassurance.

Second, some parents feel their concerns are neither listened to, nor acted upon by GPs, yet do not voice

this overtly. Conversely, some GPs believe they are good listeners, yet do not explicitly check this with

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the parent. If parents can be ‘shouting from the rooftops’, yet using words which GPs do not hear, then

perhaps the most pressing concern is using GP training, revalidation and continuing professional

development to enhance the three way communication skills between doctor, parent and child.

Future research in this area should include the accounts of older children themselves, in addition to

those of parents and doctors. More work is also needed to clarify the diagnostic processes of GPs who

correctly suspected leukaemia at an early stage, to see if these may be disseminated and incorporated

into training. Finally, our study highlights the scant evidence for how most serious illnesses present in

primary care.

Conclusion

Leukaemia is the most common malignancy in children, but is a rare occurence in primary care. Its

diagnosis requires information to be communicated to a clinician by a patient and/or parent in a way

that enables the clinician to interpret the information correctly, recognise that the child may have cancer

and consider the appropriate examination and investigations. This study identifies a wide range of non-

disease related factors potentially impeding this diagnostic process. Their attempted modification may

minimise diagnostic delay more successfully than raising awareness of red flags of leukaemia, and this

approach could be extrapolated to the other rare diseases of childhood.

What is already known on this subject

• Serious illnesses such as cancer are rare in children in primary care (about 1 in 200 children) and

are easily missed.

• Leukaemia is the most common cancer of childhood, with 4000 new cases annually in the

United States, and 450 in the United Kingdom.

• Most evidence about the presentation of paediatric leukaemia comes from secondary care, and

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little is known about how it presents in primary care.

What this study adds

• The presentation of paediatric leukaemia in primary care differs from that described in many

hospital studies. There is greater diversity and intermittency of symptoms, greater prominence

of behavioural changes, and ‘red flags’ of serious illness are frequently absent

• A wide range of non-disease related factors potentially delay the diagnosis of paediatric

leukaemia, including tensions in the doctor-patient relationship, doctors’ cognitive errors, and

systems factors such as discontinuity of care

• Reducing the diagnostic interval for childhood leukaemia requires more nuanced understanding

of how children with this disease present clinically, awareness of potential hazards in the

diagnostic reasoning process and, in some cases, greater attention to parental concerns and

more detailed clinical evaluation of unwell children

Acknowledgements

Warmest thanks to all the parents and doctors who agreed to be interviewed for this study, and the staff

of the paediatric oncology ward, who kindly helped us identify participants. We are also grateful to David

Mant, Tim Lancaster and Sandy Douglas for their helpful comments on the manuscript.

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Footnotes

Contributors

RC and MT conceived and designed the study. RC collected the data, which RC and CJ analysed. RC wrote

the first draft of the manuscript, and all authors contributed to subsequent drafts. RC is the guarantor.

Transparency statement

RC affirms that the manuscript is an honest, accurate, and transparent account of the study being

reported; that no important aspects of the study have been omitted; and that any discrepancies from the

study as planned have been explained.

Funding

This report is independent research arising from a Career Development Fellowship supported by the

National Institute for Health Research. The views expressed in this publication are those of the

author(s) and not necessarily those of the NHS, the National Institute for Health Research or the

Department of Health.

Competing interests

All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf

and declare: no support from any organisation for the submitted work; no financial relationships with

any organisations that might have an interest in the submitted work in the previous three years; no

other relationships or activities that could appear to have influenced the submitted work.

Copyright statement

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Crown copyright is claimed for this publication, in accordance with NIHR guidelines.

Ethics

Ethical approval granted by the Berkshire REC, approval number 09/H0505/36.

References

1. Buntinx F, Mant D, Van den Bruel A, Donner-Banzhof N, Dinant G-J. Dealing with low-incidence

serious diseases in general practice. British Journal of General Practice. 2011; 61(582): 43-6.

2. Feltbower RG, Lewis IJ, Picton S, Richards M, Glaser AW, Kinsey SE, et al. Diagnosing childhood

cancer in primary care - a realistic expectation? British journal of cancer. 2004; 90(10): 1882-4.

3. Ahrensberg Jm Fau - Schroder H, Schroder H Fau - Hansen RP, Hansen Rp Fau - Olesen F, Olesen

F Fau - Vedsted P, Vedsted P. The initial cancer pathway for children - one-fourth wait more than 3

months. (1651-2227 (Electronic)).

4. National Institute for Clincal Excellence. Improving outcomes in children and young people with

cancer. 2005. http://guidance.nice.org.uk/CSGCYP. Accessed 01/08/2012.

5. Mant J, Nanduri V. Role of the 2-week urgent referral pathway in childhood cancer. Archives of

Disease in Childhood. 2012.

6. Dommett RM, Redaniel MT, Stevens MC, Hamilton W, Martin RM. Features of childhood cancer

in primary care: a population-based nested case-control study. British journal of cancer. 2012; 106(5):

982-7.

7. American Cancer Society. Cancer facts and figures 2011. Atlanta: American Cancer Society;

2011.

8. Dang-Tan T, Franco EL. Diagnosis delays in childhood cancer. Cancer. 2007; 110(4): 703-13.

9. Bernbeck B, Wuller, D., Janssen, G., Wessalowski, R., Gobel, U., Schneider, D. T. Symptoms of

childhood acute lymphoblastic leukemia: red flags to recognize leukemia in daily practice. Klin Padiatr.

2009; 221(6): 369-73.

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10. Ma SK, Chan, G. C., Ha, S. Y., Chiu, D. C., Lau, Y. L., Chan, L. C. Clinical presentation, hematologic

features and treatment outcome of childhood acute lymphoblastic leukemia: a review of 73 cases in

Hong Kong. Hematol Oncol. 1997; 15(3): 141-9.

11. Thulesius H, Pola J, Håkansson A. Diagnostic Delay in Pediatric Malignancies - A Population-

based Study. Acta Oncologica. 2000; 39(7): 873-6.

12. Rajarajeswari G, Viswanathan, J. Leukemia in children. A review of 100 cases with typical clinical

manifestations. Indian Pediatr. 1980; 17(1): 37-44.

13. Dixon-Woods M, Findlay M, Young B, Cox H, Heney D. Parents' accounts of obtaining a

diagnosis of childhood cancer. The Lancet. 2001; 357(9257): 670-4.

14. Granier S, Owen, P., Pill, R., Jacobson, L. Recognising meningococcal disease in primary care:

qualitative study of how general practitioners process clinical and contextual information. BMJ. 1998;

(0959-8138 (Print)).

15. Bordage G. Why did I miss the diagnosis? Some cognitive explanations and educational

implications. Academic medicine : journal of the Association of American Medical Colleges. 1999; 74(10

Suppl): S138-43.

16. Croskerry P. The importance of cognitive errors in diagnosis and strategies to minimize them.

Academic medicine : journal of the Association of American Medical Colleges. 2003; 78(8): 775-80.

17. Royal College of Paediatrics and Child Health. Facing the future: a review of paediatric services.

. http://www.rcpch.ac.uk/system/files/protected/page/FTF%20Full.pdf. Accessed 2.04.13.

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Table 1: Characteristics of participating children with leukaemia

Age range

(years)

Child

identification

number

Sex Leukaemia type* Symptom interval (period from symptom

onset to diagnosis)

Number of GP

appointments

Number of other medical contacts

prior to diagnosis

0 - 2

1 Female ALL 5 months 7

15 Female AML 6 months 2

17 Female ALL 1 week 1 1 (Minor Injuries Unit self-referral)

3 - 6

2 Male ALL 2 months 2 1 (A&E self-referral)

3 Female ALL 5 days 1 1 (Practice nurse)


5 Female ALL 1 week 2

8 Female ALL 3 months 4 2 (A&E self-referrals)

10 Male ALL 2 months 3 3 (A&E self-referrals)

12 Male ALL 5 days 1


16 Male ALL 1 week 1 1 (Practice nurse)

7 - 10 6 Male ALL 2.5 months 2

9 Male ALL 3.5 months 1

11 - 17

7 Female ALL 3 weeks 1

11 Male AML 3 months 1

14 Male AML 3 weeks 1


* Acute lymphoblastic leukaemia (ALL), acute myeloid leukaemia (AML)

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Table 2: Pre-hospital signs and symptoms in children presenting with leukaemia, described by parents

Physical Behavioural

Infective Abnormally quiet

Chattering teeth Bad moods

Clamminess Below par

Cold Clingy

Conjunctivitis Disinterested in normal activities

Cough Excessive sleeping

Ear infection Falling asleep at school/public places

Fever Floppy

Recurrent infections Grumpy

Sore throat Impatient

Sweatiness Irritable

Uncontrollable shivering Just not right

Listless

Cutaneous/mucosal No enthusiasm for toys

Bleeding gums Not wanting to play

Bruising Reluctant to do sport

Dark shadows under eyes Tired all the time

Pallor Too well-behaved

Rash Unresponsive

Spongy gums Whingy

Yellow appearance

Musculoskeletal

Abnormally stiff gait

Arm/leg pain

Back pain

Foot pain

Joint pains

Limp

Refusal to walk

Swollen joints

Gastro-intestinal

Abdominal pain

Diarrhoea

Reduced appetite

Vomiting

Weight loss

Miscellaneous

Cold hands

Collapse

Delirium

Dizziness

Fatigue

Heavy periods

Palpitations

Shortness of breath

Wheeze

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1. DISEASE RELATED

2. NON-‐DISEASE RELATED

• Consistent with minor illness / other ‘innocent’ explanation • Inconsistent with cancer (child too well) • Worrying, but parent in denial

• Non-‐specific • Intermittent • Mimicking minor illness • Behavioural as well as ‘medical’ • Absence of early red flags

Nature of presenting signs and symptoms

• Parent defers to doctor’s judgement, against their gut instinct • Parent feels intimidated by doctor • Doctor does not take seriously parental concerns • Doctor discounts parent’s expert knowledge of child • Doctor refuses requests such as blood test • Doctor believes parent is ‘a worrier’

• Lack of continuity of care • Difficulties of accessing GP of choice • Reception staff barring access to any GP • 10 minute consultations increasing difficulties of taking blood/palpating abdomens

• Insufficient safety-‐netting • ‘Premature closure’ – doctor narrows in too early on one diagnosis • Inadequate training/experience in paediatrics • Failure to consider whole story from beginning • Threshold set too high for abdominal palpation • Threshold set too high for blood test

Figure 1: Classification of factors potentially delaying the diagnosis of paediatric leukaemia

a. PARENT FACTORS

Parents’ interpretation of symptoms

Parent-‐doctor relationship

b. DOCTOR FACTORS

Doctors’ diagnostic errors

c. SYSTEMS FACTORS

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Leukaemia early diagnosis protocol version 3, Apr 24, 2009

PROTOCOL: Improving the early recognition of leukaemia in children and adolescents

1. Investigators Dr Matthew Thompson, GP and Clinical Lecturer, Department of Primary Health Care, University of Oxford Dr Chris Mitchell, Department of Paediatric Oncology, John Radcliffe Hospital. Ms Rachel Clarke, Final Year Medical Student, University of Oxford 2. Primary research objective This study aims to address the shortfall in existing knowledge of the early presentation of leukaemia in children by exploring, through detailed interviews with parents and General Practitioners (GPs), its initial presenting symptoms and signs prior to diagnosis and hospitalisation. We aim to identify the important early clinical features of leukaemia whose prompt recognition may lead to more rapid diagnosis of the illness in children. 3. Secondary research objectives We will examine whether additional factors influence the timescale from initial clinical presentation to diagnosis, such as:

the quality and nature of the parent’s relationship with their GP parents’ attitudes about what constitutes “appropriate” behaviour consultation behaviour the GP’s knowledge of a parent’s consultation patterns and their normal degrees of anxiety

regarding their children’s health. 4. Background In the UK, more children die from cancer than from any other disease.1 Leukaemia is the largest single group of childhood cancers, accounting for approximately a third of malignancies.2 Over 400 cases are diagnosed in Britain every year.3 In recent decades, great advances have been made in the treatment of leukaemia. Yet the percentage of children cured is still only 68%, meaning that over the long-term, a third will die either from leukaemia or from the side-effects of its treatment.4 Delayed diagnoses are an important cause of potentially avoidable deaths. A recent large-scale confidential enquiry into child deaths across England, Wales and Northern Ireland found a recurring factor in avoidable deaths was “failed recognition of serious illnesses” by healthcare professionals not extensively trained in paediatrics.5 Although cancer is common in the context of serious childhood disease, a general practitioner will see, on average, a case of childhood cancer only once in his or her entire professional career.6 Furthermore, the presenting symptoms of cancers such as leukaemia in children are often vague and non-specific, mimicking those of common, self-limiting childhood illnesses (like fever, pain and vomiting).7 This lack of specificity means a GP’s index of suspicion for cancer tends to be low and hence diagnosis may be delayed. Some children with leukaemia are diagnosed only on the day they die, or even not until post-mortem. The period of diagnostic uncertainty preceding a diagnosis of cancer in a child can be extremely distressing for parents and may undermine their faith in the medical profession. It can also lead to a greater burden of disease in children before the initiation of treatment, many of which themselves have long-term toxic effects. Current knowledge about the presentation of leukaemia has been obtained largely from the results of hospital-based studies. But prompt diagnosis requires detailed understanding of the onset and evolution of signs and symptoms at a much earlier stage of presentation, in the primary care setting.

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Our study aims to address this deficit by conducting detailed interviews with parents (or other primary care-givers) and GPs which explore the sequence and development of symptoms of leukaemia in children in primary care. The interviews may throw up diagnostic pointers or “red flags” that would be useful markers of early recognition of leukaemia, applicable across the UK. They may also reveal unanticipated causes of diagnostic delay based on factors other than clinical presentation, such as parent-physician relationship and parental beliefs regarding appropriate consultation behaviour. This study will form part of a broader programme of research aiming systematically to quantify for the first time the pre-admission presentation of paediatric leukaemia. The programme will lead to guidelines and protocols which could minimize delays in diagnosing childhood cancers. 5. Methodology a) STUDY DESIGN This study will determine the early symptoms and clinical presentations of acute leukaemia in children. The study follows a “mixed methods” design, meaning that it combines both a qualitative and a quantitative approach. This methodology allows data from both approaches (the qualitative interviews and the quantitative questionnaire) to be triangulated in the analysis in order to produce greater insight than would be gained by one method alone. In particular, qualitative interviews enable individuals to speak for themselves, throwing up themes and data that were unanticipated by the researchers, thereby enriching our understanding.8 The study involves interviews with the parents of children diagnosed with leukaemia, and with the child’s GP. We will also obtain information on the clinical presentation from GP records and hospital records. b) PROTOCOL Recruitment Each time a child is diagnosed with leukaemia at the John Radcliffe Children’s Hospital, their lead doctor, the Consultant paediatric oncologist/haematologist, will judge whether it is appropriate to ask the parent(s) if they might be interviewed for this study. The risks of parents having difficulty recalling the events leading up to the diagnosis can be minimised by conducting interviews as soon as possible after diagnosis. However, the time immediately after diagnosis can be extremely stressful for parents and the Consultant may judge it inappropriate to discuss the study with parents until sufficient time has elapsed. The Consultant’s and the research team’s paramount concern will always be the well-being of the parents and children. Ideally we would like to conduct interviews within one month following initial diagnosis. If parents are willing to consider being part of the study, the Consultant will give them an information pack explaining the aims of and background to the research, and what their involvement will entail. The Consultant will stress that it is entirely their own decision whether or not to participate, and that their decision will have no bearing on their child’s treatment in any way. The information pack will include the telephone and email contact details of the researcher who will be organise and conduct the interviews. Parents can either contact the researcher themselves, or, if agreeable, the Consultant can give the researcher their contact details. Semi-structured interviews Once contact has been established with the parent, the researcher will discuss the study and, if agreeable, obtain informed consent. They will then arrange to interview the parent(s) or main carer of the affected child in a confidential relative’s room within the Children’s Hospital, at their home, or at another location if parents prefer. Interviews will be tape-recorded and transcribed verbatim. The interviews, which may last approximately 1-2 hours, will be “semi-structured”, meaning that they will be predominantly open-ended, but with a guide to ensure that a similar range topics are discussed every time.

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Initially, parents will be asked to describe the story, as they see it, from when they first noticed their child was not completely well. A time-line of the appearance of symptoms and contacts with primary health services will be established using prompts or markers of memorable dates such as Christmas, holidays or family birthdays. This will be used to help parents describe the appearance of clinical features and recall contacts with primary care. We will use the interview to explore three main areas A) initial clinical features, B) contacts with primary care, and C) the initial diagnosis of leukaemia (see below). However, it should be noted that the interviews will be open-ended from the outset. Parents will be allowed to talk freely and extensively so that the interview agenda is not fixed by the researcher. We will ask parents for basic sociodemographic data comprising of age, gender, ethnicity, and occupation of parents. The types of open ended questions that will be used to explore the main areas of interest will include some of the following questions, depending on the interview. However, these will be used as a guide to explore these three areas of interest, and not all parents will be asked all questions, they are merely a guide for the interviewr:: A) Initial clinical features

When did you first think there was something wrong with your child or that they weren’t 100% themselves?

What was it about them that made you think something was wrong? What else did you notice about their symptoms? Did the symptoms get worse or new symptoms start to appear? Describe the changes in as

much detail as possible. What was the main thing you were concerned about and why? What made you first think about going to see a doctor? Did anything put you off going to see your GP (or another doctor) about this problem, or

going back to see them again? At this early stage, before you’d seen a doctor, what did you think was wrong with your

child? B) Contacts with primary care

Tell me as much as possible about what you remember from that first appointment with your GP for this illness?

How did your GP help you? How seriously do you feel your concerns were taken? How many times did you see your GP between then and when you were referred to the

hospital? Can you remember what happened each time? How were you feeling at this stage? What was happening to your child? Were their symptoms changing/evolving/getting worse? Did you decide at some stage to go to A&E or another doctor/service, and what was it that

prompted you to do this? Did your GP arrange a blood test for your child? Did you ask for this or did your GP suggest

it? C) Diagnosis of leukaemia

At what stage did you first think your child might have leukaemia? Did your GP mention leukaemia when they referred you?

Do you remember when when leukaemia was mentioned? Tell me what you knew about leukaemia before your child was diagnosed? Did you have any idea how leukaemia might affect a child, or what to look for to spot the

illness in a child? What happened once the diagnosis was made? Once leukaemia was diagnosed, how did this make you feel about the period that led up to

the diagnosis? How do you feel about the way your GP managed the situation/assessed your

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child/addressed your concerns? Reflecting now on what happened, is there anything you wish had happened differently? Is there anything you think other parents should know about diagnosing leukaemia in a

child? Is there anything you think GPs or other doctors should consider? What do you think was done well by your GP/other health professionals involved in this

early stage of your child’s diagnosis, and what do you think should be done differently? During the interview the researcher will fill out a questionnaire with the parent, based on a systematic review of the literature, which will ask parents to recall whether a list of up to 30 different symptoms were present before hospital admission, and if possible if they can recall when they first appeared: Tick if present Approximately when

did it first appear? Pale Tired Not interested in things Less energy than usual Crying more, or change in their cry Joint pain Leg pain Arm pain New or unusual bruising New or unusual bleeding Rash on skin Lumps or swelling in the neck Lumps or swelling in another part of the body

Tummy pain Lump or swelling in the tummy Confused Headache. If so, was it worse in the morning?

Being unsteady on their feet Change in vision Double vision Nausea. If so, was it worse in the morning?

Vomiting If so, was it worse in the morning?

Difficulty sleeping Difficulty breathing Wheezing Difficulty walking Aching all over Drowsy or more sleepy than usual Any other symptoms not noted above? List up to 5 At the completion of the first interview, parents will be asked if they would consider being re-interviewed at a later date, should new themes emerge as the study continues. If in agreement,

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they may be telephoned by the researcher at a future point in the study. Parents who do not agree to any further interviews will not be approached again. c) GENERAL PRACTITIONERS The researcher will also contact the child’s GP by letter, explaining the nature of the study and requesting permission to access the child’s medical record and to interview the GP about how the child presented to them. If the GP agrees, the researcher will arrange to interview them at their practice or at another location the GP prefers. The GP will be asked to examine their records of consultations with this child. We will obtain additional information from those records such as the patient’s consultations for this illness, medications, past medical history. Semi-structured interviews with GPs Below is a list of the types of questions which will be used in the interviews with GPs. These will be used to piece together as comprehensive an account as possible of the child’s early presentation to primary care. We will use open ended questions with the GP to identify the initial clinical features, and attempt to identify the reasons for suspecting leukaemia or referring the child. GPs will be encouraged to talk freely and extensively so that the interview agenda is not fixed by us from the outset. The content of these interviews will include the following, depending on that particular patient and GP

How well do you know this child? When did you first think there might be something seriously wrong with this child? What was it about them that made you think something was wrong? What else did you notice about their symptoms? What was the main thing you were concerned about and why? Did you arrange a blood test on this child, if so what was the main thing prompting you to

do this? When did you think about referring them to paediatrics? What was the main thing that

prompted you to do this? Did the parents seem to be more worried than usual about this child? Do you recall if the

parents were worried about a serious disease in particular? Is there anything that you wished you had done differently in the care of this child?

d) DATA OBTAINED FROM HOSPITAL RECORDS AND GP RECORDS We will ask the parent’s permission at time of consenting to participate in the study to review both their GP records, as well as their hospital records. GP records will be reviewed, with consent of the GP (see section c), in order to obtain information about the following:

Details of consultations in the 12 months prior to diagnosis, including clinical features, diagnosis, investigations, treatments, advice.

Current medications and those used in the previous 12 months prior to diagnosis Illnesses recorded in the past medical history.

Hospital records will be examined and will be used to obtain the following information:

clinical features recorded of the child at time of diagnosis or admission to hospital Type of leukaemia and course of illness.

e) INCLUSION CRITERIA Parent(s) of children up to 16 years old who have been diagnosed within the previous month with leukaemia and referred to the John Radcliffe Children’s Hospital for treatment.

- 5 -

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- 6 -

The GP of the child, or the GP at the child’s practice who is most familiar with the child. f) EXLCUSION CRITERIA We will exclude parents of children with a previous diagnosis of malignancy of any kind, parents who are unable or unwilling to participate, and those unavailable for follow-up. Parents will not be excluded on the basis of their first language not being English. We will obtain interpreters whenever necessary. g) SAMPLE SIZE Formal sample size calculations have not been performed. In qualitative research, of which this study is an example, it is usual to stop interviewing when a thorough understanding of the area understanding has been reached, an end-point known as saturation.9 The research is saturated when new interviews no longer elicit new themes or issues not already raised by previous participants. We anticipate that approximately 30 to 50 interviews with parents and GPs will be sufficient for this study. h) DATA ANALYSIS All interviews will be transcribed verbatim. A thematic analysis of the interview data will be conducted by the researcher responsible for the data collection. This means that the interviews will be read and re-read throughout the study period, identifying key themes and issues. The data will be entered into a specialist software package, which will be used to help organise and analyse emergent (ie unexpected) themes as well as those that were anticipated. Passages of text will be “coded” or labelled according to each theme identified. To ensure rigorous data protection, the original audio-recordings of parent interviews and their written transcripts will be stored securely according to Departmental and University protocols. All material from parent interviews will be identified only using a unique study code, protecting participants anonymity. All information gathered from the interviews will be treated in strict confidence. Interviews with GPs will also be transcribed within 2 weeks of collection. The transcripts will be examined by Dr Thompson and any information that could be used to identify the GP or GP practice will be removed. There will be no link between the GP interviews and the identity of the child. Analysis of the questionnaires will consist of calculating the simple frequencies of individual clinical features and combinations of clinical features. This will be stratified by age and type of leukaemia if necessary. Data analysis will take place in the Department of Primary Health Care. Archiving of material will be performed according to Department and University protocols 6. Funding Funding for this study has been obtained from the NIHR National School for Primary Care Research. 7. References

1. Bleyer WA. The impact of childhood cancer on the United States and the world. CA Cancer. J Clin. 1990; 40:355-367

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2 Swerdlow AJ, dos Santos Silva I, Doll R (2001). Cancer Incidence and Mortality in England and Wales: Trends and Risk Factors, p 181-193. Oxford: Oxford University Press 3 Stiller CA, Kroll ME, Eatock EM (2007) Vh 5 Survival from childhood cancer. In Childhood Cancer in Britain: Incidence, Surivvial, Mortality, Stiller CA (ed), p 131-204. Oxford: Oxford University Press 4 Shah A et al. Childhood leukaemia:long-term excess mortality and the proportion “cured”. Br J of Cancer. 2008. 99. 219-223 5 Pearson, G. Why Children Die. A report of a pilot confidential enquiry into child deaths by CEMACH. Clin Risk 2008; 14: 166-168. 6 Morland B. Childhood cancer: what are the danger symptoms and signs? The New Generalist. Vol 1, 3, autumn 2003p 12-14. 7 Haimi M et al. Delay in diagnosis of children with cancer: a retrospective study of 315 children. Paediatric Hematology and Oncology, 21: 37-48, 2004. 8 Kuper, A et al. An introduction to reading and appraising qualitative research. BMJ. 2008; 337: 404-407. 9 Kuper A et al. Critically appraising qualitative research. BMJ. 2008; 337: a1035

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“Shouting from the roof tops”: a qualitative study of how children with leukaemia are diagnosed in primary care

Journal: BMJ Open

Manuscript ID: bmjopen-2013-004640.R1

Article Type: Research

Date Submitted by the Author: 22-Jan-2014

Complete List of Authors: Clarke, Rachel; John Radcliffe Hospital, Acute General Medicine Jones, Caroline; University of Oxford, Primary Care Health Sciences Mitchell, Christopher; John Radcliffe Hospital, Department of Paediatric Oncology/Haematology Thompson, Matthew; University of Oxford, Department of Primary Care Health Sciences

<b>Primary Subject Heading</b>:

Diagnostics

Secondary Subject Heading: Paediatrics, Haematology (incl blood transfusion), Qualitative research

Keywords: Leukaemia < HAEMATOLOGY, Leukaemia < ONCOLOGY, Paediatric oncology < ONCOLOGY, Paediatric oncology < PAEDIATRICS, QUALITATIVE RESEARCH


BMJ Open on D

ecember 7, 2020 by guest. P

rotected by copyright.http://bm

jopen.bmj.com

/B

MJ O

pen: first published as 10.1136/bmjopen-2013-004640 on 18 F

ebruary 2014. Dow

nloaded from



1

TITLE PAGE


primary care




Jones, Caroline H D






Thompson, Matthew J

Helen D. Cohen endowed Professor of Family Medicine, University of Washington, Seattle, USA. WA

98195-4696 & Senior Clinical Research Fellow, Department of Primary Care Health Sciences, University

of Oxford, Radcliffe Observatory Quarter, Woodstock Road, Oxford, OX2 6GG


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1, Chris Mitchell


1

Abstract

Objectives



Design


Setting


Participants


leukaemia.

Results








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Conclusions










GPs.








illness.

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Introduction






diagnosis.2

















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5

We aimed to identify disease and non-disease related factors which facilitate or impede diagnosis of

paediatric cancer, by exploring the period leading to diagnosis of leukaemia through narrative interviews

with parents and GPs of newly diagnosed children. We chose to investigate diagnosis of leukaemia for a

number of reasons. It is the most common malignancy of childhood, with an annual incidence of nearly

4000 cases in the United States and 450 cases in the UK, and is responsible for a third of child cancer

deaths.7 Leukaemia represents a major diagnostic challenge for primary care clinicians as the disease

symptomatology is diverse, affects all body systems, and mimics common childhood illnesses. Moreover,

the time from symptom onset to diagnosis ranges from one day to several months, but is typically

several weeks, suggesting considerable scope for improvement in speed of diagnosis.8

Methods

Design


their own terms, and potentially raise issues not anticipated by the researchers. Ethical approval for the

study was granted by the Berkshire Research Ethics Committee.

Sample











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before each interview was recorded. Recruitment was stopped once saturation was reached (i.e. new


Data collection












actions, and their views of any factors which may have influenced the diagnostic pathway. New topics





Data analysis





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Results




















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infrequent.







child 11)







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9

























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right’:














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anxiety:




15)










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child 8).

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14

Discussion

Main findings


























abdomens.

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We have classified some of the key findings above in terms of whether they are disease or non-disease

related factors impeding diagnosis (figure 1). We believe this is a valuable conceptual framework for

thinking about rare illnesses since it highlights the full range of factors potentially influencing speed to

diagnosis, rather than the presenting features of the illness alone.








backgrounds, and GPs with various levels of experience.










In





No studies, to our




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16




doctor’s decisions, bypassing the GP’s role as gatekeeper to secondary care, or asking for a blood test.

Our findings demonstrate clearly how doctors’ cognitive errors can potentially delay diagnosis in primary

care. For example, some GPs decided early in the illness process that they knew the underlying cause of

the child’s symptoms (a minor illness) and therefore did not actively seek alternative diagnoses – so-

called ‘premature closure’.16


‘Red flag’ based algorithms for aiding diagnosis of paediatric cancers such as leukaemia may be of

limited value, given its frequently non-specific and fluctuating early features. Our results concur with a

recent case control study of primary care records in the UK, which found that the alert signs identified in

NICE guidance for childhood cancer were recorded more commonly in cases than controls, yet that only

a quarter of cases had any alert symptoms recorded in the three months prior to diagnosis.4, 6

Clinicians

should also be aware that non-disease related factors are potentially drivers of diagnostic delay. Specific

practical implications might include GPs having a lower threshold for taking blood in children, examining

young children’s abdomens more readily, and introducing a system whereby any children presenting

more frequently than usual, trigger more detailed scrutiny by clinicians. More generally, current UK GP

training, in which only 40% of trainees experience a hospital paediatrics placement, should be reformed

so that all GP trainees have core paediatric training.17

On-going professional development should build

skills and confidence in examining and taking blood from young children.


unique significance for diagnosing rare childhood illnesses in general practice. ‘Listening to the parent’ is

something of a mantra in paediatrics; our findings highlight in addition the importance of what is unsaid

between parent and clinician in shaping the diagnostic pathway. First, some doctors and parents silently

take their cue from each other as to how anxious they should be themselves, with the concomitant risk

of false reassurance. Second, some parents feel their concerns are neither listened to, nor acted upon by

GPs, yet do not voice this overtly. Conversely, some GPs believe they are good listeners, yet do not

explicitly check this with the parent. If parents can be ‘shouting from the rooftops’, yet using words

which GPs do not hear, then perhaps the most pressing concern is using GP training, revalidation and

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17

continuing professional development to enhance the three way communication skills between doctor,

parent and child.





primary care.

Conclusion

Leukaemia is the most common malignancy in children, but a rare occurence in primary care. Its









are easily missed.





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Acknowledgements




Footnotes

Contributors



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Funding





Competing interests





Copyright statement


Ethics


Data sharing

Additional data will not be shared, since these comprise original interview transcripts, whose publication

would endanger participant confidentiality.

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References

1. Buntinx F, Mant D, Van den Bruel A, et al. Dealing with low-incidence serious diseases in

general practice. British Journal of General Practice. 2011; 61(582): 43-6.

2. Feltbower RG, Lewis IJ, Picton S, et al. Diagnosing childhood cancer in primary care - a realistic

expectation? British journal of cancer. 2004; 90(10): 1882-4.

3. Ahrensberg Jm Fau - Schroder H, Schroder H Fau - Hansen RP, Hansen Rp Fau - Olesen F, Oet al.

The initial cancer pathway for children - one-fourth wait more than 3 months. (1651-2227 (Electronic)).





6. Dommett RM, Redaniel MT, Stevens MC, et al. Features of childhood cancer in primary care: a

population-based nested case-control study. British journal of cancer. 2012; 106(5): 982-7.


2011.


9. Bernbeck B, Wuller, D., Janssen, G., et al. Symptoms of childhood acute lymphoblastic

leukemia: red flags to recognize leukemia in daily practice. Klin Padiatr. 2009; 221(6): 369-73.

10. Ma SK, Chan, G. C., Ha, S. Y., et al. Clinical presentation, hematologic features and treatment

outcome of childhood acute lymphoblastic leukemia: a review of 73 cases in Hong Kong. Hematol

Oncol. 1997; 15(3): 141-9.







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14. Granier S, Owen, P., Pill, R., et al. Recognising meningococcal disease in primary care:


(0959-8138 (Print)).



Suppl): S138-43.





Figure 1. Classification of factors potentially delaying the diagnosis of paediatric leukemia

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22

Table 1: Characteristics of participating children with leukaemia

Age range

(years)

Child

identification

number

Sex Leukaemia type* Symptom interval (period from symptom

onset to diagnosis)

Number of GP

appointments

Number of other medical contacts

prior to diagnosis

0 - 2


15 Female AML 6 months 2

17 Female ALL 1 week 1 1 (Minor Injuries Unit self-referral)

3 - 6


3 Female ALL 5 days 1 1 (Practice nurse)


5 Female ALL 1 week 2

8 Female ALL 3 months 4 2 (A&E self-referrals)

10 Male ALL 2 months 3 3 (A&E self-referrals)

12 Male ALL 5 days 1


16 Male ALL 1 week 1 1 (Practice nurse)

7 - 10 6 Male ALL 2.5 months 2

9 Male ALL 3.5 months 1

11 - 17

7 Female ALL 3 weeks 1


14 Male AML 3 weeks 1


* Acute lymphoblastic leukaemia (ALL), acute myeloid leukaemia (AML)

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23

Table 2: Pre-hospital signs and symptoms in children presenting with leukaemia, described by parents

Physical Behavioural

Infective Abnormally quiet

Chattering teeth Bad moods

Clamminess Below par

Cold Clingy

Conjunctivitis Disinterested in normal activities

Cough Excessive sleeping

Ear infection Falling asleep at school/public places

Fever Floppy

Recurrent infections Grumpy

Sore throat Impatient

Sweatiness Irritable

Uncontrollable shivering Just not right

Listless

Cutaneous/mucosal No enthusiasm for toys

Bleeding gums Not wanting to play

Bruising Reluctant to do sport

Dark shadows under eyes Tired all the time

Pallor Too well-behaved

Rash Unresponsive

Spongy gums Whingy

Yellow appearance

Musculoskeletal

Abnormally stiff gait

Arm/leg pain

Back pain

Foot pain

Joint pains

Limp

Refusal to walk

Swollen joints

Gastro-intestinal

Abdominal pain

Diarrhoea

Reduced appetite

Vomiting

Weight loss

Miscellaneous

Cold hands

Collapse

Delirium Dizziness

Fatigue

Heavy periods

Palpitations

Shortness of breath

Wheeze

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1

TITLE PAGE


primary care




Jones, Caroline H D






Thompson, Matthew J

Helen D. Cohen endowed Professor of Family Medicine, University of Washington, Seattle, USA. WA

98195-4696 & Senior Clinical Research FellowReader in Primary Care, Department of Primary Care

Health Sciences, University of Oxford, Radcliffe Observatory Quarter, Woodstock Road, Oxford, OX2

6GG


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1, Chris Mitchell


1

Abstract

Objectives



Design


Setting


Participants


leukaemia.

Results






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Conclusions










GPs.








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illness.





Introduction






diagnosis.2













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We aimed to identify disease and non-disease related factors which facilitate or impede diagnosis of

paediatric cancer, by exploringe the period leading to diagnosis of leukaemia through narrative

interviews with parents and GPs of newly diagnosed children.of paediatric cancer, in order to identify the

disease and non-disease related factors which facilitate or impede diagnosis. We conducted narrative

interviews with parents and GPs of children presenting with a new diagnosis of leukaemia. We chose to

investigate diagnosis of leukaemia for a number of reasons. It Leukaemia is the most common

malignancy of childhood, with an annual incidence of nearly 4000 cases in the United States and 450

cases in the UK, and is responsible for a third of child cancer deaths.7 Leukaemia represents a major

diagnostic challenge for primary care clinicians as the disease symptomatology is diverse, affects all body

systems, and mimics common childhood illnesses. " Moreover, the time from symptom onset to

diagnosis ranges from one day to several months, but is typically several weeks, suggesting considerable

scope for improvement in speed of diagnosis.8

Methods

Design


their own terms, and potentially raise issues not anticipated by the researchers. Ethical approval for the

study was granted by the Berkshire Research Ethics Committee.

Sample

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6















before each interview was recorded. Recruitment was stopped once saturation was reached (i.e. new


Data collection











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actions, ; and their views of any factors which may have influenced the diagnostic pathway. New topics





Data analysis










Results









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infrequent.


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child 11)


















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right’:




















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anxiety:




15)













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child 8).

Discussion

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Main findings


























abdomens.

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We have classified some of the key findings above in terms of whether they are disease or non-disease

related factors impeding diagnosis (figure 1). We believe this is a valuable conceptual framework for

thinking about rare illnesses since it highlights the full range of factors potentially influencing speed to

diagnosis, rather than the presenting features of the illness alone.








backgrounds, and GPs with various levels of experience. Data were analysed by a doctor and a non-

clinical researcher: their different prior knowledge, assumptions and perspectives strengthened the

analysis.










In




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No studies, to our







doctor’s decisions, bypassing the GP’s role as gatekeeper to secondary care, , using the internet to make

a diagnosis of leukaemia themselves, or asking for a blood test. Our findings demonstrate clearly how

doctors’ cognitive errors can potentially delay diagnosis in primary care. For example, some GPs decided

early in the illness process that they knew the underlying cause of the child’s symptoms (a minor illness)

and therefore did not actively seek alternative diagnoses – so-called ‘premature closure’.16


Our findings suggest that ‘Rred flag’ based algorithms for aiding diagnosis of paediatric cancers such as

leukaemia may be of limited value, given its frequently non-specific and fluctuating early features. Our

results concur with those of a recent case control study of primary care records in the UK, which found

that the alert signs identified in NICE guidance for childhood cancer were recorded more commonly in

cases than controls, yet that only a quarter of cases had any alert symptoms recorded in the three

months prior to diagnosis.4, 6

CInstead, clinicians should also be sensitive to the factaware that non-

disease related factors such as errors in doctors’ cognitive reasoning, tensions in the doctor-parent

relationship, and systems factors such as lack of continuity of care are all potentially drivers of diagnostic

delay. Specific practical implications might include GPs having a lower threshold for taking blood in

children, examining young children’s abdomens more readily, and introducing a system whereby any

children presenting frequently, or more frequently than usual, trigger more detailed scrutiny by

clinicians. More generally, current UK GP training, in which only 40% of trainees experience a hospital

paediatrics placement, should be reformed so that all GP trainees have core paediatric training.17

On-

going professional development should build skills and confidence in examining and taking blood from

young children.

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unique significance for diagnosing rare childhood illnesses in general practice. In the absence of hard

clinical signs of disease, when the patient is too young to express themselves verbally, and when parents

have exclusive insight into their child’s well-being based on their years of parenting, a doctor’s abilities to

communicate well with the parent are paramount. ‘Listening to the parent’ is something of a mantra in

paediatrics; our findings highlight in addition the importance of what is unsaid between parent and

clinician in shaping the diagnostic pathway. First, some doctors and parents silently take their cue from

each other as to how anxious they should be themselves, with the concomitant risk of false reassurance.

Second, some parents feel their concerns are neither listened to, nor acted upon by GPs, yet do not voice

this overtly. Conversely, some GPs believe they are good listeners, yet do not explicitly check this with

the parent. If parents can be ‘shouting from the rooftops’, yet using words which GPs do not hear, then

perhaps the most pressing concern is using GP training, revalidation and continuing professional

development to enhance the three way communication skills between doctor, parent and child.





primary care.

Conclusion

Leukaemia is the most common malignancy in children, but is a rare occurence in primary care. Its







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are easily missed.
















Acknowledgements

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Footnotes

Contributors







Funding





Competing interests

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Copyright statement


Ethics


References

1. Buntinx F, Mant D, Van den Bruel A, Donner-Banzhof N, Dinant G-J. Dealing with low-incidence

serious diseases in general practice. British Journal of General Practice. 2011; 61(582): 43-6.

2. Feltbower RG, Lewis IJ, Picton S, Richards M, Glaser AW, Kinsey SE, et al. Diagnosing childhood

cancer in primary care - a realistic expectation? British journal of cancer. 2004; 90(10): 1882-4.

3. Ahrensberg Jm Fau - Schroder H, Schroder H Fau - Hansen RP, Hansen Rp Fau - Olesen F, Olesen

F Fau - Vedsted P, Vedsted P. The initial cancer pathway for children - one-fourth wait more than 3

months. (1651-2227 (Electronic)).





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6. Dommett RM, Redaniel MT, Stevens MC, Hamilton W, Martin RM. Features of childhood cancer

in primary care: a population-based nested case-control study. British journal of cancer. 2012; 106(5):

982-7.


2011.


9. Bernbeck B, Wuller, D., Janssen, G., Wessalowski, R., Gobel, U., Schneider, D. T. Symptoms of

childhood acute lymphoblastic leukemia: red flags to recognize leukemia in daily practice. Klin Padiatr.

2009; 221(6): 369-73.

10. Ma SK, Chan, G. C., Ha, S. Y., Chiu, D. C., Lau, Y. L., Chan, L. C. Clinical presentation, hematologic

features and treatment outcome of childhood acute lymphoblastic leukemia: a review of 73 cases in

Hong Kong. Hematol Oncol. 1997; 15(3): 141-9.







14. Granier S, Owen, P., Pill, R., Jacobson, L. Recognising meningococcal disease in primary care:


(0959-8138 (Print)).



Suppl): S138-43.





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Figure 1. Classification of factors potentially delaying the diagnosis of paediatric leukemia 127x90mm (300 x 300 DPI)

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PROTOCOL: Improving the early recognition of leukaemia in children and adolescents

1. Investigators Dr Matthew Thompson, GP and Clinical Lecturer, Department of Primary Health Care, University of Oxford Dr Chris Mitchell, Department of Paediatric Oncology, John Radcliffe Hospital. Ms Rachel Clarke, Final Year Medical Student, University of Oxford 2. Primary research objective This study aims to address the shortfall in existing knowledge of the early presentation of leukaemia in children by exploring, through detailed interviews with parents and General Practitioners (GPs), its initial presenting symptoms and signs prior to diagnosis and hospitalisation. We aim to identify the important early clinical features of leukaemia whose prompt recognition may lead to more rapid diagnosis of the illness in children. 3. Secondary research objectives We will examine whether additional factors influence the timescale from initial clinical presentation to diagnosis, such as:

the quality and nature of the parent’s relationship with their GP parents’ attitudes about what constitutes “appropriate” behaviour consultation behaviour the GP’s knowledge of a parent’s consultation patterns and their normal degrees of anxiety

regarding their children’s health. 4. Background In the UK, more children die from cancer than from any other disease.1 Leukaemia is the largest single group of childhood cancers, accounting for approximately a third of malignancies.2 Over 400 cases are diagnosed in Britain every year.3 In recent decades, great advances have been made in the treatment of leukaemia. Yet the percentage of children cured is still only 68%, meaning that over the long-term, a third will die either from leukaemia or from the side-effects of its treatment.4 Delayed diagnoses are an important cause of potentially avoidable deaths. A recent large-scale confidential enquiry into child deaths across England, Wales and Northern Ireland found a recurring factor in avoidable deaths was “failed recognition of serious illnesses” by healthcare professionals not extensively trained in paediatrics.5 Although cancer is common in the context of serious childhood disease, a general practitioner will see, on average, a case of childhood cancer only once in his or her entire professional career.6 Furthermore, the presenting symptoms of cancers such as leukaemia in children are often vague and non-specific, mimicking those of common, self-limiting childhood illnesses (like fever, pain and vomiting).7 This lack of specificity means a GP’s index of suspicion for cancer tends to be low and hence diagnosis may be delayed. Some children with leukaemia are diagnosed only on the day they die, or even not until post-mortem. The period of diagnostic uncertainty preceding a diagnosis of cancer in a child can be extremely distressing for parents and may undermine their faith in the medical profession. It can also lead to a greater burden of disease in children before the initiation of treatment, many of which themselves have long-term toxic effects. Current knowledge about the presentation of leukaemia has been obtained largely from the results of hospital-based studies. But prompt diagnosis requires detailed understanding of the onset and evolution of signs and symptoms at a much earlier stage of presentation, in the primary care setting.

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Our study aims to address this deficit by conducting detailed interviews with parents (or other primary care-givers) and GPs which explore the sequence and development of symptoms of leukaemia in children in primary care. The interviews may throw up diagnostic pointers or “red flags” that would be useful markers of early recognition of leukaemia, applicable across the UK. They may also reveal unanticipated causes of diagnostic delay based on factors other than clinical presentation, such as parent-physician relationship and parental beliefs regarding appropriate consultation behaviour. This study will form part of a broader programme of research aiming systematically to quantify for the first time the pre-admission presentation of paediatric leukaemia. The programme will lead to guidelines and protocols which could minimize delays in diagnosing childhood cancers. 5. Methodology a) STUDY DESIGN This study will determine the early symptoms and clinical presentations of acute leukaemia in children. The study follows a “mixed methods” design, meaning that it combines both a qualitative and a quantitative approach. This methodology allows data from both approaches (the qualitative interviews and the quantitative questionnaire) to be triangulated in the analysis in order to produce greater insight than would be gained by one method alone. In particular, qualitative interviews enable individuals to speak for themselves, throwing up themes and data that were unanticipated by the researchers, thereby enriching our understanding.8 The study involves interviews with the parents of children diagnosed with leukaemia, and with the child’s GP. We will also obtain information on the clinical presentation from GP records and hospital records. b) PROTOCOL Recruitment Each time a child is diagnosed with leukaemia at the John Radcliffe Children’s Hospital, their lead doctor, the Consultant paediatric oncologist/haematologist, will judge whether it is appropriate to ask the parent(s) if they might be interviewed for this study. The risks of parents having difficulty recalling the events leading up to the diagnosis can be minimised by conducting interviews as soon as possible after diagnosis. However, the time immediately after diagnosis can be extremely stressful for parents and the Consultant may judge it inappropriate to discuss the study with parents until sufficient time has elapsed. The Consultant’s and the research team’s paramount concern will always be the well-being of the parents and children. Ideally we would like to conduct interviews within one month following initial diagnosis. If parents are willing to consider being part of the study, the Consultant will give them an information pack explaining the aims of and background to the research, and what their involvement will entail. The Consultant will stress that it is entirely their own decision whether or not to participate, and that their decision will have no bearing on their child’s treatment in any way. The information pack will include the telephone and email contact details of the researcher who will be organise and conduct the interviews. Parents can either contact the researcher themselves, or, if agreeable, the Consultant can give the researcher their contact details. Semi-structured interviews Once contact has been established with the parent, the researcher will discuss the study and, if agreeable, obtain informed consent. They will then arrange to interview the parent(s) or main carer of the affected child in a confidential relative’s room within the Children’s Hospital, at their home, or at another location if parents prefer. Interviews will be tape-recorded and transcribed verbatim. The interviews, which may last approximately 1-2 hours, will be “semi-structured”, meaning that they will be predominantly open-ended, but with a guide to ensure that a similar range topics are discussed every time.

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Initially, parents will be asked to describe the story, as they see it, from when they first noticed their child was not completely well. A time-line of the appearance of symptoms and contacts with primary health services will be established using prompts or markers of memorable dates such as Christmas, holidays or family birthdays. This will be used to help parents describe the appearance of clinical features and recall contacts with primary care. We will use the interview to explore three main areas A) initial clinical features, B) contacts with primary care, and C) the initial diagnosis of leukaemia (see below). However, it should be noted that the interviews will be open-ended from the outset. Parents will be allowed to talk freely and extensively so that the interview agenda is not fixed by the researcher. We will ask parents for basic sociodemographic data comprising of age, gender, ethnicity, and occupation of parents. The types of open ended questions that will be used to explore the main areas of interest will include some of the following questions, depending on the interview. However, these will be used as a guide to explore these three areas of interest, and not all parents will be asked all questions, they are merely a guide for the interviewr:: A) Initial clinical features

When did you first think there was something wrong with your child or that they weren’t 100% themselves?

What was it about them that made you think something was wrong? What else did you notice about their symptoms? Did the symptoms get worse or new symptoms start to appear? Describe the changes in as

much detail as possible. What was the main thing you were concerned about and why? What made you first think about going to see a doctor? Did anything put you off going to see your GP (or another doctor) about this problem, or

going back to see them again? At this early stage, before you’d seen a doctor, what did you think was wrong with your

child? B) Contacts with primary care

Tell me as much as possible about what you remember from that first appointment with your GP for this illness?

How did your GP help you? How seriously do you feel your concerns were taken? How many times did you see your GP between then and when you were referred to the

hospital? Can you remember what happened each time? How were you feeling at this stage? What was happening to your child? Were their symptoms changing/evolving/getting worse? Did you decide at some stage to go to A&E or another doctor/service, and what was it that

prompted you to do this? Did your GP arrange a blood test for your child? Did you ask for this or did your GP suggest

it? C) Diagnosis of leukaemia

At what stage did you first think your child might have leukaemia? Did your GP mention leukaemia when they referred you?

Do you remember when when leukaemia was mentioned? Tell me what you knew about leukaemia before your child was diagnosed? Did you have any idea how leukaemia might affect a child, or what to look for to spot the

illness in a child? What happened once the diagnosis was made? Once leukaemia was diagnosed, how did this make you feel about the period that led up to

the diagnosis? How do you feel about the way your GP managed the situation/assessed your

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child/addressed your concerns? Reflecting now on what happened, is there anything you wish had happened differently? Is there anything you think other parents should know about diagnosing leukaemia in a

child? Is there anything you think GPs or other doctors should consider? What do you think was done well by your GP/other health professionals involved in this

early stage of your child’s diagnosis, and what do you think should be done differently? During the interview the researcher will fill out a questionnaire with the parent, based on a systematic review of the literature, which will ask parents to recall whether a list of up to 30 different symptoms were present before hospital admission, and if possible if they can recall when they first appeared: Tick if present Approximately when

did it first appear? Pale Tired Not interested in things Less energy than usual Crying more, or change in their cry Joint pain Leg pain Arm pain New or unusual bruising New or unusual bleeding Rash on skin Lumps or swelling in the neck Lumps or swelling in another part of the body

Tummy pain Lump or swelling in the tummy Confused Headache. If so, was it worse in the morning?

Being unsteady on their feet Change in vision Double vision Nausea. If so, was it worse in the morning?

Vomiting If so, was it worse in the morning?

Difficulty sleeping Difficulty breathing Wheezing Difficulty walking Aching all over Drowsy or more sleepy than usual Any other symptoms not noted above? List up to 5 At the completion of the first interview, parents will be asked if they would consider being re-interviewed at a later date, should new themes emerge as the study continues. If in agreement,

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they may be telephoned by the researcher at a future point in the study. Parents who do not agree to any further interviews will not be approached again. c) GENERAL PRACTITIONERS The researcher will also contact the child’s GP by letter, explaining the nature of the study and requesting permission to access the child’s medical record and to interview the GP about how the child presented to them. If the GP agrees, the researcher will arrange to interview them at their practice or at another location the GP prefers. The GP will be asked to examine their records of consultations with this child. We will obtain additional information from those records such as the patient’s consultations for this illness, medications, past medical history. Semi-structured interviews with GPs Below is a list of the types of questions which will be used in the interviews with GPs. These will be used to piece together as comprehensive an account as possible of the child’s early presentation to primary care. We will use open ended questions with the GP to identify the initial clinical features, and attempt to identify the reasons for suspecting leukaemia or referring the child. GPs will be encouraged to talk freely and extensively so that the interview agenda is not fixed by us from the outset. The content of these interviews will include the following, depending on that particular patient and GP

How well do you know this child? When did you first think there might be something seriously wrong with this child? What was it about them that made you think something was wrong? What else did you notice about their symptoms? What was the main thing you were concerned about and why? Did you arrange a blood test on this child, if so what was the main thing prompting you to

do this? When did you think about referring them to paediatrics? What was the main thing that

prompted you to do this? Did the parents seem to be more worried than usual about this child? Do you recall if the

parents were worried about a serious disease in particular? Is there anything that you wished you had done differently in the care of this child?

d) DATA OBTAINED FROM HOSPITAL RECORDS AND GP RECORDS We will ask the parent’s permission at time of consenting to participate in the study to review both their GP records, as well as their hospital records. GP records will be reviewed, with consent of the GP (see section c), in order to obtain information about the following:

Details of consultations in the 12 months prior to diagnosis, including clinical features, diagnosis, investigations, treatments, advice.

Current medications and those used in the previous 12 months prior to diagnosis Illnesses recorded in the past medical history.

Hospital records will be examined and will be used to obtain the following information:

clinical features recorded of the child at time of diagnosis or admission to hospital Type of leukaemia and course of illness.

e) INCLUSION CRITERIA Parent(s) of children up to 16 years old who have been diagnosed within the previous month with leukaemia and referred to the John Radcliffe Children’s Hospital for treatment.

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The GP of the child, or the GP at the child’s practice who is most familiar with the child. f) EXLCUSION CRITERIA We will exclude parents of children with a previous diagnosis of malignancy of any kind, parents who are unable or unwilling to participate, and those unavailable for follow-up. Parents will not be excluded on the basis of their first language not being English. We will obtain interpreters whenever necessary. g) SAMPLE SIZE Formal sample size calculations have not been performed. In qualitative research, of which this study is an example, it is usual to stop interviewing when a thorough understanding of the area understanding has been reached, an end-point known as saturation.9 The research is saturated when new interviews no longer elicit new themes or issues not already raised by previous participants. We anticipate that approximately 30 to 50 interviews with parents and GPs will be sufficient for this study. h) DATA ANALYSIS All interviews will be transcribed verbatim. A thematic analysis of the interview data will be conducted by the researcher responsible for the data collection. This means that the interviews will be read and re-read throughout the study period, identifying key themes and issues. The data will be entered into a specialist software package, which will be used to help organise and analyse emergent (ie unexpected) themes as well as those that were anticipated. Passages of text will be “coded” or labelled according to each theme identified. To ensure rigorous data protection, the original audio-recordings of parent interviews and their written transcripts will be stored securely according to Departmental and University protocols. All material from parent interviews will be identified only using a unique study code, protecting participants anonymity. All information gathered from the interviews will be treated in strict confidence. Interviews with GPs will also be transcribed within 2 weeks of collection. The transcripts will be examined by Dr Thompson and any information that could be used to identify the GP or GP practice will be removed. There will be no link between the GP interviews and the identity of the child. Analysis of the questionnaires will consist of calculating the simple frequencies of individual clinical features and combinations of clinical features. This will be stratified by age and type of leukaemia if necessary. Data analysis will take place in the Department of Primary Health Care. Archiving of material will be performed according to Department and University protocols 6. Funding Funding for this study has been obtained from the NIHR National School for Primary Care Research. 7. References

1. Bleyer WA. The impact of childhood cancer on the United States and the world. CA Cancer. J Clin. 1990; 40:355-367

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2 Swerdlow AJ, dos Santos Silva I, Doll R (2001). Cancer Incidence and Mortality in England and Wales: Trends and Risk Factors, p 181-193. Oxford: Oxford University Press 3 Stiller CA, Kroll ME, Eatock EM (2007) Vh 5 Survival from childhood cancer. In Childhood Cancer in Britain: Incidence, Surivvial, Mortality, Stiller CA (ed), p 131-204. Oxford: Oxford University Press 4 Shah A et al. Childhood leukaemia:long-term excess mortality and the proportion “cured”. Br J of Cancer. 2008. 99. 219-223 5 Pearson, G. Why Children Die. A report of a pilot confidential enquiry into child deaths by CEMACH. Clin Risk 2008; 14: 166-168. 6 Morland B. Childhood cancer: what are the danger symptoms and signs? The New Generalist. Vol 1, 3, autumn 2003p 12-14. 7 Haimi M et al. Delay in diagnosis of children with cancer: a retrospective study of 315 children. Paediatric Hematology and Oncology, 21: 37-48, 2004. 8 Kuper, A et al. An introduction to reading and appraising qualitative research. BMJ. 2008; 337: 404-407. 9 Kuper A et al. Critically appraising qualitative research. BMJ. 2008; 337: a1035

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