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MARC-35: Prospective Cohort Study of Severe Bronchiolitis and Risk of Recurrent Wheezing

Frequently Asked Questions

GENERAL

Q: What kind of training is required?
A: There are a number of training elements required prior to the start of the study.  All study personnel who will be involved in patient enrollment must complete the training relevant to their role in MARC-35 prior to enrolling patients.  The training components include:

  • General training (including REDCap training)
  • REDCap training
  • PRACTICE REDCap database use
  • NPA Sample Collection Video
  • Nasal Swab Collection Video
  • Review of the Manual of Procedures (MOP)

Visit the “Training Materials” section of the EMNet website for these materials. If you do not have access to REDCap, please let us know.

Site PIs must initial the Training Log to certify that all study staff have completed these pre-study training elements.

Q: What about secondary analyses – are site investigators allowed to write manuscripts?
A: Yes! We encourage you to pursue any and all secondary analyses that interest you. The primary analyses will describe the development of a tool to help physicians determine which children with bronchiolitis are more likely to develop recurrent wheezing or will be at a higher risk for asthma. There are, of course, many other directions you could go with the vast amount of data that we will collect. Throughout all of our studies, we at EMNet have always encouraged investigators to publish secondary analyses using network data. Since 1997, more than 500 different EMNet investigators have published > 350 peer-reviewed publications. Please check out the Publications section of the EMNet website (www.emnet-usa.org) for more details. You can access our secondary analysis proposal page at the following address: www.emnet-usa.org/Coordinating_Center/SAPF.cfm. This is not a list of papers, but rather an opportunity for you to propose a paper based on whatever aspect(s) of the data interest you the most. EMNet statisticians will perform the analysis for you and the entire team will work on your national presentation and then manuscript publication.

Q: How do I report a protocol deviation?
A: Please fill out the Protocol Deviation Form in REDCap.  If the protocol deviation is considered “major” according to protocol definitions, complete the form and email Ashley Sullivan immediately.  All major protocol violations must be reported to the NIAID Medical Officer within 48 hours. Please also follow your local IRB protocol deviation reporting requirements.

Q: How do I report an adverse event?
A: Please fill out the Adverse Event (AE) Form in REDCap as soon as you become aware of an AE and email Ashley Sullivan immediately.  In the case of a serious AE (SAE), the NIAID Medical Officer will be notified by the overall study Principal Investigator no later than 24 hours after the site becomes aware of a SAE related to the study procedure.  Please see the study protocol for details about AE severity, grading, and attribution.  Please follow your local IRB adverse event reporting requirements.

Q: Is it mandatory for families to review the introductory video?
A: No. We do encourage that families watch the introductory video because some sites have told us that it was helpful in answering basic questions and "selling" the study. It is short (4-minute) video that provides useful information and also provides some legitimacy to the study. Ultimately, however, it's just meant to help you.

REDCap

Q: What browser should I use for filling out forms in REDCap?
A: REDCap has a tendency to freeze in Internet Explorer. We recommend that you use Mozilla Firefox or Google Chrome. If you must use Internet Explorer, please save your work frequently!

Q: Can I edit a form in REDCap after filling it out?
A: Yes.  If you find additional data that you had previously left as “Not Documented” or “Missing,” you can log in to REDCap and change or add these data. This is true even if the form was marked as complete.

Q: Why does an error message pop-up saying that my entry into a data form is not valid?
A: Some answer boxes are validated and will only accept an answer to a question in a certain format. For example if one tries to enter admission date as 11/22 it is not be considered a valid entry. Instead, the date should be entered as 11/22/2012.

Q: What does it mean when my record is classified as either complete, unverified or incomplete?
A. You should mark a form as “complete” if data entry is complete; no additional data need to be entered. Mark the form as “unverified” if data entry is partially complete and there are fields pending responses. “Incomplete” communicates that no data have been entered.

Q: Why does the following error message pop-up when I am entering data (see example below)?

A: This warning appears when you have entered data into a field (“Field B”) that appeared due to an answer in another field (“Field A”) but you have changed the value in “Field A” such that “Field B” is no longer applicable and will therefore no longer appear. REDCap warns you that it will delete the data you have entered into “Field B” when this field disappears from view. Click OK if to confirm that the data in “Field B” may be deleted.  To avoid the display of this pop-up message each time you access this form, click “Reset Value” in the lower right-hand corner of “Field B” before you change your response to “Field A”.

Q: Why does REDCap show a warning message when I enter the correct name for child in “Confirm First Name” or “Confirm Last Name” fields at the start of each form?
A: These fields are case-sensitive. Make sure that you are capitalizing the first letter and mimicking the capitalization used in the Intake Form (data entry points to which REDCap checks these variables).

Q: What should I do when I get an error message because I have too many tabs open in REDCap?
A: Usually, if you click the browser “Back” button, you can retrieve entered information from the cache. Then, close the other tabs and save the form again.

ENROLLMENT  

Q: Why does the consent occur after the screening?
A: The consent process is longer than the screening process so it is important to make sure the child is eligible BEFORE taking up their time with the consent.

Q: Can someone other than the site PI obtain consent from a legal guardian/parent?
A: Yes. Sites should follow their site-specific rules on who can obtain informed consent.

Q: If a parent refuses the nasopharyngeal aspirate, can we include them in the study?
A: If a parent refuses the nasal aspirate, we will not include them in the study.  The virology of severe bronchiolitis is a critical component of the study. The parent must consent to the nasopharyngeal aspirate to participate in this study.

Q: If a parent refuses the blood draw, can we include them in the study?
A: If a parent refuses the blood draw, we will not include them in the study since the blood test results are an important study component.  The parent must consent to the blood draw to participate in this study.

Q: How many patients are we required to enroll?
A: In year 3 each site will enroll at least 30 study participants with at least 6 from the ICU from November 1 – April 30. The site will be responsible for determining how many study participants will be recruited each month during the enrollment period to ensure they meet this goal. Monthly variation in the overall number of children admitted to the hospital with bronchiolitis as well as children admitted to the ICU is expected, with the highest number of admissions occurring in December, January and February.  We estimate that ~10% of participants who are enrolled will not fulfill enrollment requirements or will not meet the run-in requirements; these participants do not count towards your enrollment goal and so you may need to over-enroll to meet your recruitment goal of at least 30 participants. 

Q: What happens if an enrolled patient from the ward is transferred into the ICU?
A: They become an ICU patient.

Q: At our site, it is easier for us to consent, enroll and especially collect specimens in the ED after a clinical decision has been made to admit a child. Are we allowed to enroll and collect specimens like NPA and blood in the ED?
A. Patients must be admitted to the medical floor at some point during the encounter but you may consent, enroll, and collect specimens in the ED once the decision has been made to admit the child. If this is the case, the admission time you record on the forms will be AFTER you have collected the biological specimens.  For this study, admission time is the time of arrival onto the floor/ward/ICU.  

Q: Can we enroll children who acquire bronchiolitis while in the hospital?
A: No, please exclude children with nosocomial bronchiolitis.

Q: What happens to patients who are not fully enrolled, including those who did not have a large enough blood sample?
A: Participants who are not fully enrolled will not be part of the acute or chronic cohort; they will not contribute additional nasal swabs, be contacted for follow-up interviews or have their medical records reviewed annually. However, information and specimens from those participants should not be discarded; their information and samples still have value. Specimens for these participants should be mailed to MGH where we will determine the value/usability of each specimen.  Remember that participants consent to the use of their specimens and information even if they are later found ineligible.

Q: If potential participants become ineligible or withdraw, should we reassign study ID numbers so that they are sequential?
A: No, please leave the study IDs as they are. They do not need to be sequential.

FORMS

Screening Form
Q: For whom do you begin a screening form?
A: You should begin a screening form for any child <1 year who is admitted to your hospital with bronchiolitis during the months of screening. This means that you will enter in all patients admitted to the ICU for the entire recruitment period (November through April) but you only need to enter children admitted to the ward with bronchiolitis from December through February. However, any child on the ward you should approach outside of the months December through February should be entered into the Screening Database. For each child you will record whether the child was approached, missed, or known to be ineligible based on a pre-screen. If the child was missed or known to be ineligible, you will describe why participant was missed or ineligible and the form is complete. If you approached the child, you should continue with the form. Please ask all questions on the form, even if a patient’s answer makes them ineligible for the study.

Q: Why is there an option to select ≥1 as a reason why the patient was ineligible? I thought we only entered participants who were less than 1 year old?
A: That is true. You should are only entering patients who are less than 1 year old into the registry but we have left this option here in the unlikely event that it is needed. We do not anticipate anyone selecting this as a reason for ineligibility.

Q: How often should we update the screening database?
Screening forms for those participants who you approach should be filled out in real-time. Ideally, screening forms for those who are missed or ineligible should be entered every day but if that is not possible, you should make sure to do it at least once per week. The EMNet Coordinating Center monitors the screening database regularly.

Q: Do we need to fill out the screening forms on weekends if, from a personnel standpoint, we are not going to be able to enroll patients on weekends or on holidays (Thanksgiving Day, Christmas Day, etc)?
A: You should fill out a Screening Form for ALL children under the age of 1 admitted to your hospital with an attending physician diagnosis of bronchiolitis. If you are unable to approach a patient on a weekend or holiday, you should fill out a Screening Form when you return for any patients you missed. If a patient came in over the weekend and was not approached, you should answer the first question on the Screening Form as "No, missed." and select the reason why. This will ensure we have an accurate picture of the number of children under the age of 1 admitted to your hospital with bronchiolitis.

Q: What are the inclusion and exclusion criteria?
A:  
Inclusion criteria:

  • Age younger than 1 year
  • Physician-diagnosis of bronchiolitis
  • Ability of the parent/legal guardian to give informed consent ≤ 24 hours after child’s admission to hospital or ICU
  • Parent/legal guardian willing to provide permanent address, phone number, email address, alternate contact information and PCP contact information
  • Ability of parent/legal guardian to speak English or Spanish

Exclusion criteria:

  • Enrolled into this bronchiolitis study during an earlier hospital admission
  • Parent/legal guardian does not agree to the collection of the NPA or blood specimen or possible future use of the specimen
  • Patient transferred to a participating site hospital >48 hours after the original time of admission to another hospital
  • Time transferred to site hospital >24  hours
  • Current treatment is 2nd oral steroid course in 6 months, or 4th episode of wheezing in past year (i.e., already meets the primary endpoint)
  • Known heart-lung disease, immunodeficiency, immunosuppression, or gestational age <32 weeks
  • Insurmountable language barrier

Q: Is there a list of acceptable admission diagnoses for patients that we can use (ie: Asthma, RAD) if bronchiolitis is not an admission diagnosis? 
A: The attending physician must diagnose the child as having bronchiolitis (defined by the American Academy of Pediatrics as acute respiratory illness with some combination of rhinitis, cough, tachypnea, wheezing, crackles, and retractions). However, the admission diagnosis could be RAD, cough, wheeze, etc. and the site team should approach the attending to ask if the child in question really has bronchiolitis and not RAD, cough, wheeze, etc. If the attending, however, insists on diagnosing RAD, then the child would not meet the inclusion criteria.  Verbal confirmation that the child has bronchiolitis from the attending physician is acceptable; it does not need to be a written diagnosis. If you obtain verbal confirmation that the child has bronchiolitis but it is not documented in the chart, please make a note in the Comment box on the Intake Form.

Q: One of the exclusion criteria is known heart-lung disease. What about hemodynamically insignificant lesions which may resolve (i.e., PDA, ASD, small muscular VSDs)?
A: Hemodynamically insignificant lesions are fine. We introduce the exclusion criteria for more serious congenital heart disease that causes shortness of breath, cyanosis, etc (i.e., heart disease that would complicate bronchiolitis management and/or result in cardiorespiratory problems during first 6 years of life). We want to look at shortness of breath, for example, and not wonder if it's caused by asthma or by the congenital heart disease. Please let that be your guide.

Q: What are the requirements for providing contact information?
A: Participants must provide a permanent address, phone number, email address, alternate contact information, and primary care provider and should expect that this information will not change in the next 12 months. However, parents/legal guardians who are college students, whose current residence may not be their permanent residence or may not be at their current address for the next 12 months, may be enrolled assuming they meet all other inclusion criteria.  Military personnel not expecting to be deployed in the next 12 months may also be enrolled, assuming they meet all other inclusion criteria. And finally, families who plan to move locally in the next 12 months (i.e. the move is local enough they will not need to change their PCP) may also be enrolled.

Q: What information will be required for the participant’s alternate contact?
A: Participants should provide as much contact information about the alternate contact as they can; however, only a phone number is required for the alternate contact. If a participant cannot provide complete information about the alternate contact during the intake interview or wish to ask the alternate’s permission first, they may provide the alternate contact information at the 1-week follow-up call. However, if this information cannot be provided by the completion of the 1-week call, the participant cannot continue in the study.

Q: Does PCP need to be a specific individual or can it be a clinic with multiple providers if parent does not identify a single person?
A: A clinic with multiple providers is fine.

Q: What admission date and time should we enter on the Screening Form? Should it be time of arrival onto the floor/ward/ICU as is required on forms in the Participant Database?
A: For many sites, time of arrival onto the floor/ward/ICU will also be the official admission date and time recorded by the hospital and therefore will be used on both the Screening Form and in the Participant Database. Please contact us if recording the time of arrival onto the floor/ward/ICU on the Screening Form is not feasible at your site. It is essential that EMNet understands exactly what is being recorded on the Screening Form as the admission date and time at each site.

Intake Form
Q: Does time from admission to enrollment include time spent in the ED if patient came through ED?
A: Parents/legal guardians will be approached about participating after the medical team has finished their assessments and stabilized the study participant. If necessary, the recruiting will take place the morning after admission, but no later than 24 hours after admission to the ward or ICU (Protocol, pg 15). Ideally, the admission time should be the time at which the patient arrives to the actual ward or ICU. You have 24 hours to enroll the patient from the admission time. For many of you, the official hospital admission time will be the same as the time when the patient arrives on the floor of the ward or ICU. We realize, however, that some hospitals may not record the arrival time on the floor (e.g., they consider time of bed assignment as the "official" admission time). If this is the case at your hospital, please use as the study "time 0" the time of the initial assessment by the inpatient nursing team. This will be very shortly after arrival onto the floor. It is very important to remember that the vital signs at INITIAL admission on the Inpatient Form should be those that were taken on arrival to the medical floor, not any vitals taken in the ED (regardless of boarding status).

If you have a patient who is officially admitted but still in the ED (i.e., ED boarder) but being treated and seen by the inpatient team, please let us know and we can discuss how to handle this situation on a case-by-case basis. As you can see, "admission time" seems like an easy concept but it can get very complicated!

Q: Race and ethnicity seem a bit complicated. How do I answer these questions?
A: We follow NIH policy on recording race and ethnicity. Every person is either of Hispanic, Latino or Spanish origin or they are not of Hispanic, Latino, or Spanish origin. Every person also has a race (or races). A person who is Hispanic can be of any race and a person of any race can be of Hispanic, Latino or Spanish origin or not of Hispanic, Latino, or Spanish origin. If a person reports multiple races, you should enter them all. If someone reports other, please ask follow-up questions to determine what race they are and specify that in the space provided. See the MOP for definitions of each race group. If someone refuses to answer, select the “refuse” option and in the space provided, please use any information available to you to inform us as to the race of the child.

Q: Many forms ask for admission time. Which time would you like recorded: the time the decision was made to admit the patient, the time the order was put in to admit the patient, or the time the patient was transported to the floor?
A: Please record the time the patient was transported to the floor.

Q: Question 18 asks if the child stopped breathing during this illness. Is this same as apnea, or something more severe (i.e. need for resuscitation)?
A: This is the parent's view of "stopped breathing." If a parent thinks their child has stopped breathing, the answer is yes. True apnea will only be able to be observed by physicians.

Q: Question 29 asks if the child's immunizations are up to date for his/her age.  How delayed can be considered as normal (e.g., if postponed by recurrent infections)?
A: If the immunizations are obtained within 2 weeks of the due date, we consider the immunizations up to date.

Q: In Question 34, the parent wasn’t able to provide me with an exact date of the breathing problem episode.  What should I enter in the date field?
A: Some questions require that the parent/legal guardian provide a date of an event (e.g., the date of a breathing problem).  Given the young age at which children are enrolled in the study (median age is 4 months), these hospitalizations and ED visits often are very significant events as far as the parents are concerned and so we find that they do remember the dates. That said, we recognize that some parents may not remember the EXACT dates. In this case, you should work with the parent to approximate the date to the best of their ability. If they are not willing to provide an approximate date, ask them in which month the event occurred.  If they cannot identify the precise day in that month that the event occurred, enter the day as the 15th (i.e., the middle of the month). Ultimately, we'll have the medical records and can figure it out more precisely.

Q: In Question 34, how should I classify an urgent care center?
A: If the child visited an urgent care clinic that is not open 24/7, then choose “Other.” If it is open 24/7, then it can be considered an emergency room.

Q: In Question 34, when would I check “Other” as a type of healthcare visit for a breathing problem?
A: If you do not see the type of healthcare provider that the child visited for the breathing problem, you should check this option. For example, if a child went to a clinic (not a PCP office), you would choose “Other.”

Q: Questions 46 and 48 ask about selected medical conditions of the biological mother and father.  What do I record if the mother or father says that they used to have a condition, but not longer have it?
A: Check all of the conditions that the biological mother or father reports that she/he currently has or has had in the past.  If the respondent believes that a condition has “gone away” (e.g., the mother definitely had asthma as a child, but thinks she has outgrew it during adolescence), please record it.  The condition does not have to be doctor-diagnosed, but one that the biological mother or father thinks she/he has.

Q: The participant’s parent has a history of exercise-induced asthma. How should I classify it in Question 46a?
A: This should be classified as “All year.”

Intake Chart Review Form
Q: When should the Intake Chart Review Form be completed?
A: The Intake Chart Review From may be completed anytime after the Intake Interview.

Q: If the lab results are not yet received should I wait to complete the Intake Chart Review Form?
A: You have two options. You could go ahead and complete what you can, save the form as “Unverified” if you’re working in REDCap, and come back to fill in the lab results when they become available. Or you can wait until you have the lab results before you begin the form. Please remember that the Intake Chart Review Form asks about preadmission labs.  All values for the lab section of the form should be from ED, outpatient visit, or day of transfer only.

Q: What is the acceptable timing for CBC results?
A:  A participant must have a CBC with diff performed either less than 24 hours before being admitted to your hospital (i.e. in the ED, clinic, or transfer hospital) OR at some point during admission to your hospital in order to be fully enrolled in the study. If a CBC with diff is not performed, the participant is not fully enrolled in the study and will not participate in follow-up.  Pre-admission CBC results from blood drawn in the ED, clinic or at transferring hospital will be entered into the Intake Chart Review. CBC results from blood drawn after admission (arrival onto the floor) will be entered into the Inpatient Form. For some participants, a CBC with diff will be performed both during pre-admission and admission. Please record the information in the appropriate sections.

Q: What happens if a patient arrives from the clinic without clinic data?
A: If a patient is seen in a clinic, sent to the ED, and then admitted to your hospital, use the data from your ED to answer the questions on the Intake Chart Review. If there is any data about wheezing available from the clinic, use that information as well. For example, if wheezing was documented in clinic and not in the ED, you should “carry forward” that documentation of wheezing and record it on the Intake Chart Review. 

Q: We enrolled a subject who was initially seen at another ED and then transferred to our ED before being admitted. We do not have vitals and values from the outside ED. What values should we enter into the form?
A: You should use the initial vitals and information available from your ED to fill out the Intake Chart Review form.

Q: We enrolled a subject who visited an ED at an outside hospital, was admitted into that hospital, and then visited our ED and was admitted to our hospital (EDoutside -> INPToutside ->EDenrolling ->INPTenrolling). How are the different sections of the Intake Chart Review form supposed to be filled out?
A:
Question 64
1. Please answer “Yes” and record the date and time that the patient visited the ED at the enrolling hospital.
2. In the “Comments” box at the end of the form, please record the date and time of transfer from the outside hospital (the date and time that the patient left the outside hospital).
Initial vital signs
Please record vital signs measured in the ED of the enrolling hospital. We would like the vital signs that are recorded here to be those taken closest to the time of admission into the enrolling hospital.
Questions 66-82 (Pre-admission clinical data)
Please record data from the enrolling hospital, if possible. If the only data available are from the outside hospital, please record them here; and in the “Comments” box, please note which data are from the outside hospital. However, if wheezing is documented from the outside hospital but not the enrolling hospital, please “carry forward” this information and record it in Question 70.
Question 83 (Pre-admission lab results)
Please record lab results from the enrolling hospital, if possible. If the only lab results available are from the outside hospital, please record them here; and in the “Comments” box, please note which lab results are from the outside hospital.
Question 84 (Virology testing)
If more than one set of virology results is available, please record the results from the testing done closest to the time of admission to the enrolling hospital.

Q: What do I do if a participant completes enrollment (interview, specimen collection, etc.) but then withdraws later in the index hospitalization, before being discharged home?
A: In the unlikely event that this occurs, please answer “Yes” to Question 62 on the Intake Form: “Did the patient withdraw consent from the study before completing the assessment?” Please explain when the withdrawal occurred as well as the reason for withdrawal (if ascertainable). Remember that you should not ship any biospecimens for participants who withdrew at any point in the index hospitalization. We understand that the assessment was in fact completed but this will capture those individuals for whom we should not have biospecimens or contact for the 1-week follow-up and future follow-up calls.

Contact Form
Q: Can I enter a P.O. Box as a permanent address?
A: Yes, as long as there is also a stable home address. Enter the home address in the comments box at the end of the Contact Form.

Q: The manual of procedures says that I should try calling the phone number given by the parent/legal guardian.  Why?
It’s important that we be able to reach all participants by phone for study follow-up.  All participants must have working phones.  After the Contact Form is complete, the RA should try the phone number the subject identified as being the best to use to reach them once to confirm that it is in service (i.e., make sure the phone rings).  If the parent designates that their cell phone is the best number, it’s likely that they will have their cell phone with them.  Explain to the parent that you are going to test the number to make sure it works and that you’ve copied down the number correctly.  If the phone number is not in service, the RA should re-approach the subject to resolve the problem.  If the line is inconsistent or inactive, the RA will remind the subject that he/she needs an active line to participate in the study.  If the issue remains unresolved, the subject should not continue in the study.  In such a case, the subject should be marked as “enrolled but found to be later ineligible” on the Intake Form.  

Q: Is an email address really required? I’m worried that participants at my site won’t have an email address and therefore won’t be able to participate.
A: An email address is very important to study follow-up. EMNet frequently contacts participants via email to schedule follow-up calls, send thank you notes, and information about payment, among other things. Email addresses are very common these days, especially among younger individuals like many of the parents who are enrolling in the study. There was a very interesting study performed recently at an urban, academic pediatric ED that serves a predominately minority and economically disadvantaged population that found that 483 out of 503 participants (96%) had an email address (Saidinejad M, Teach SJ, Chamberlain JM. Internet access and electronic communication among families in an urban pediatric emergency department. Pediatric Emergency Care. 2012 Jun;28(6):553-7 22653452).

Q: If parent does not have a SSN or does not want to give SSN, can they give the child's and have payment made to the child instead?
A: Unfortunately, no. According to MGH policies we cannot provide payment for the follow-up phone calls to the child instead of the parent.

Specimen Enrollment Checklist
Q: How much blood should I collect from each participant?
A: You should collect between 5 and 15ml from each participant. If you reach 5ml and still have a good flow, you should keep going, up to 15ml. If you are just barely able to collect 5ml and cannot get any more with that draw, please do not re-stick the child to try to obtain additional blood. The child has met the minimum requirement to participate in the study. Remember that if you are unable to obtain the 5ml minimum even after additional attempts, you must contact Ashley (afsullivan@partners.org) to discuss a waiver.

The total volume of blood obtained from a participant should be a maximum of 15ml between the amount obtained in the draw plus the amount you can obtain from discarded bloods.  For example, if you are able to obtain the 6ml from the draw, you can collect up to 9ml of discarded blood. Or if you obtain 4ml and get a waiver, you can collect up to 11ml of discarded blood.

Q: Can I use discarded blood to meet my minimum requirement of 5ml?
A: You can use discarded blood from a red top tube to meet your minimum requirement of 5ml. You should collect discarded bloods from any tube type available but only red top tube blood may count towards your minimum requirement. If you fill out the Specimen Enrollment Checklist for a participant for whom you are unable to draw enough blood to obtain a waiver (at least 3ml) and mark the participant as not fulfilling enrollment requirements but later acquire discarded blood from a red top tube that is enough to make them eligible, you should return to the Specimen Enrollment Checklist and change their status to “fully enrolled.” Please only modify the status at the end of the Specimen Enrollment Checklist as it relates to specimen collection. For example, if the participant is found ineligible for some other reason later, do not change the status on the Specimen Enrollment Checklist.

Q: Is a CBC with differential required for each participant? If a CBC with differential has not been ordered in the course of normal assessment does it need to be ordered in order to continue enrollment?
A: Yes, a CBC with diff must be performed either less than 24 hours before admission or at some point during admission. If it has not been ordered for clinical purposes then it must be ordered for research purposes.  Please determine if a CBC has been ordered before blood specimen is drawn. The cost of performing this research test locally is covered in the site budget.  If you have questions about whether or not a CBC with diff qualifies, please contact us.

Q: If a patient is transferred from another hospital where a CBC was performed, do I need to order another CBC once they are admitted to my hospital?
A: If a CBC with diff was performed within 24 hours of admission (either at transferring hospital, in ED or clinic), then you do not need to order another CBC as part of the study protocol. If an additional CBC with diff is run during the hospital stay, great. There is a place to record both of these CBCs on the Intake Chart Review and the Inpatient Form.

If a CBC with diff was performed more than 24 hours before admission then you should order one and record the results on the Inpatient Form. If a CBC with diff is ordered as part of patient care upon admission, which is not uncommon, you do not need to order an additional one. 

If no CBC with diff was ordered prior to admission, you must make sure one is ordered, either by you or the medical team, during the hospitalization and record the results on the Inpatient Form. 

Q: Occasionally blood clots.  What happens if blood is collected into the red top and can be spun for serum and plasma but the CBC clots and has no result? Should we collect additional blood for a repeat CBC?  If a family refuses a second blood draw for a repeat CBC, are they withdrawn from the study? 
A: If blood for a CBC clots, you should attempt to collect an additional 0.5ml of blood to repeat the test. You might consider trying a finger-stick (if allowed by your IRB) for the second CBC as parents are sometimes more agreeable to the idea. If a parent refuses a second blood draw for a repeat CBC or if you cannot obtain the blood for whatever reason, they are considered unable to fulfill enrollment requirements according to the Specimen Enrollment Checklist and will not participate in any follow-up. Please do not consider them to have withdrawn. The withdraw status should only be used if the parent formally asks for their child to be withdrawn from the study.

Q: Does the NPA need to be taken before the index nasal swab?
A: Ideally the NPA would be collected before the index nasal swab. However, in situations where this is not possible (i.e. the child will be discharged less than 2 hours after collecting the NPA), the nasal swab can be collected before the NPA. If you collect the NPA before the nasal swab, remember you must wait at least 2 hours before collecting the nasal swab.

Q: Is a blood from a heel stick acceptable as an index specimen?
A: Yes as long as you are IRB approved to collect blood from a heel stick.

Q: What happens if blood sample is less than the minimum volume (5mL)?
A: Please ask participant’s parent or legal guardian if you may perform an additional blood draw.  If this is not possible or is unsuccessful and the total volume of blood drawn is between 3 and 5 mL then you must contact Ashley Sullivan immediately about obtaining a waiver. If the total volume of blood drawn is less than 3mL then the participant must stop enrollment as the participant does not meet the minimum blood volume requirement.

Q: Do you have any suggestions for which biospecimen I try to collect first?
A: We have found that collecting an adequate volume of blood is often the most difficult part. We suggest attempting the blood draw first, if time allows. Remember you have 24 hours from the time of admission (arrival onto the floor) to collect an NPA so you might need to do that first to allow the NPA to be collected in the correct time window.

Q: What should I do if the participant refuses to allow a blood draw/ nasopharyngeal aspirate/ nasal swab?
A: These biospecimens are required for participation in the study. If participant refuses then you should stop enrollment for this participant.  Select “No” for whichever specimen(s) were not collected and “Participant did not fulfill enrollment requirements.” Explain that the parent refused collection of the biospecimen(s) in the Comment Box. 

One Week Follow-up Form
Q: What is the window of time during which the follow-up phone call may be made?
A: The calls must be made between 8 and 14 days after the patient’s discharge from the hospital. It is important that the first attempt be made on day 8 to ensure all participants have equal opportunity to be reached. Beginning calls on the 8th day (i.e., closer to the time you last saw them) should improve your chances of reaching the patient. Calls made after 14 days will be considered ineligible and follow-up data collected from an ineligible call will not be usable.

Q: How many times should I attempt to contact a participant for their one week follow-up interview before classifying them as “Unreachable?”
A: You should call them at least 5 times over at least three days before deciding that they are unreachable.

Q: How should follow-up with non-English-speaking people be handled?
A: If the person with whom the initial visit interview is performed prefers to conduct follow-up in Spanish then they will have indicated this preference in the Contact Form in REDCap. This will alert you to the possibility that you may have to use a bilingual research staff person or your hospital’s interpreter services for the call. The follow-up forms have been translated into Spanish to assist Spanish-speaking researchers in making the follow-up calls. Please note that any charges for this service will need to be covered by your budgeted funds; the EMNet Coordinating Center will not pay for an interpreter service.

Q: How should I handle situations where a parent's response to a question on the follow-up form about medications prescribed conflicts with what is documented in the chart?
A: Please record the parent's response. If a parent reports that their child is not taking a medicine prescribed at discharge, they may not have filled the prescription.

Q: Is it possible to complete 1-week PCP contact information (in the Contact Form) after the one-week follow up call?
A: No, you must collect this information during or before the one-week follow up call. It is the responsibility of site personnel to look up all necessary contact information even if the subject only provides the PCP name.

Q: If the one week follow-up window overlaps with the subject’s 6- or 12-month window, should we conduct both interviews at the same time?
A:  If this happens, please contact us to determine how to handle the situation. The 6- and 12-month interviews take place at the EMNet Coordinating Center and we will need to determine how to complete the calls.

Q: If a patient is readmitted after discharge within their one-week follow-up call window, how should the one-week call be completed?
A: The one-week call should be completed as scheduled 8-14 days after initial discharge. If the participant is readmitted to the hospital during this follow-up window, you may consider completing the one-week interview in person. In addition, if a child is readmitted after having ≥24 hours since discharge where he/she “looked good” but then worsened and was readmitted, remember to do a healthcare swab and readmission form for the participant. If the child is readmitted <24 hours after the previous hospitalization, then a healthcare swab and readmission form do not need to be completed; we will consider this as part of the index admission. If you run into a situation where the one-week call window overlaps with the three-week call window (e.g., the child has been in hospital for 2+ weeks), please let EMNet know and we will discuss how to handle the specific situation.

SPECIMENS

Q: What do I do if a participant does not agree to the genetic testing portion of the study?
A: Consent to the genetic portion of the study is optional. A participant may decline participation in the genetic portion of the study but still be enrolled into the main study. You will indicate whether or not they consented to the genetic portion in the Screening Form.  If a participant declines the genetic testing portion of the study, the blood collected from this participant will be processed in the same manner as someone who consents to genetic testing. The pellets from individuals who do not consent to genetic testing will be sent to MGH, instead of the University of Arizona. 

Q: Where do I note whether or not the participant consented to the optional genetic testing?
A: After reviewing the consent form with the participant, you should return to the Screening Form and answer yes or no to whether or not consent was obtained. If yes, answer the follow-up question of whether or not the child was consented to the genetics portion of the study.

Q: Can we store blood at 4C before putting into -80C?
A: Yes. If a -80C freezer is not easily accessible or you are not able to process the blood right away, you may store the blood at 4C within 1 hour of collection. However, the blood must be processed and transferred to a -80C freezer within 24 hours of collection.

Q: How long should we wait after a previous suctioning before collecting the NPA sample?
A: Please wait 1-2 hours.

Q: What should you do if you can only collect the NPA sample from a single nostril?
You may only be able to collect the sample from a single nostril if an ICU patient's nares are occupied by ET tubes or feeding catheters. Please instill 1 cc in the available nostril and then suction up 2 ccs from the sterile cup. (The procedure therefore uses 1 less cc of saline than normal for the two-nostril NPA collection procedure.) When the specimen is collected from one nostril, please record this fact on both the vial and sample shipment log. On the sample shipment log, please put an asterisk next to the sample with an explanation of the asterisk at the bottom of the sample log.

Q: How should we take the NPA sample if the patient is intubated or on CPAP?
A: If a patient is intubated or on CPAP you should still collect the NPA through the nose.

Q: Some of the tubes of viral transport media (VTM) in my refrigerator have frozen on the mid-level setting. Is it okay to use the VTM after it has been frozen?
A: Yes, you can still use the VTM after it has been frozen.

Q: How long can the VTM be outside of the refrigerator before it becomes unusable?
A:  You should avoid leaving the VTM outside of the refrigerator as much as possible. If you accidentally leave the VTM out of the refrigerator for a few hours, that is okay but anything left at room temperature for more than 2-3 days should be discarded. The VTM loses its stability after extended periods of time at room temperature.

Q: When should we give the clearance swab kit and ARI swab kit to the parents?
A: Please give the kits to the parents as soon as possible after enrollment. Many hospital stays for bronchiolitis are very short (only a day or two).

Q: When should I mail the nasal swabs?
A: Nasal swabs should be mailed immediately after collection in the nasal swab kit box provided. Each box is pre-paid and pre-addressed and requires no special certification to ship. The kit box should be mailed through regular USPS mail.

Q: What should we do with any discarded bloods we are able to obtain? Do we just freeze it as is or do we centrifuge it and aliquot it into aliquot tubes?
A: Regardless of tube type, all discarded bloods should be transferred to one of the blue or plain cap tubes that have been provided for storage at -80C, not in the green, lavender, etc. top tube they were collected in. Affix one of the generic labels provided to each tube before storage. The label lists the study ID, tube type, date and time collected, and date stored at -80C. Spinning of discarded red top tube blood is optional (unless it is used to meet your 5ml minimum, then it is required). Please do not spin discarded blood from other tube types.

READMISSION

Q:  There is a readmission intake form.  Are we responsible for re-interviewing ALL readmissions? 
A: Yes, you should make every effort to administer the re-admission forms for any child who is enrolled in the study and re-admitted to your hospital for a breathing problem until the child reaches age 1 year.  Keep in mind that this does not happen that frequently.  If for some reason, a participant is admitted and discharged before you are able to approach them to complete the interview portion of the re-admission forms, you can still complete the chart review portion of the form.  Make a note in the Comment Box about why the interview portion is blank.

Q: When do we fill out readmission forms?
A: Hospital readmissions should only be considered in this study when the patient is admitted for a breathing problem.

Q: Are there any special mailing requirements for nasal swabs collected for children who are re-admitted?
A: If a child is re-admitted to the hospital, an ARI swab should be completed as this is a breathing problem that resulted in a healthcare visit. Staff should ask parents if they have collected the ARI swab and if not, offer any help or assistance parents need in collecting it. Study staff may collect the swab for the parents. These swabs should be mailed in the same manner as all other swabs.

IRB

Q: Privacy’ refers to a person’s desire to control access of others to themselves. Describe the steps that will be taken to protect and assure the privacy of the subject.  Detail specific actions the Research Team will take to ensure that privacy is protected through each phase of the study (e.g. access to medical records for recruitment, mailings to subjects, phone calls with subjects, research visits).
A: At enrollment the research team will approach all children age <1 year admitted to the hospital with bronchiolitis. We will identify these potential participants by scanning the diagnoses from the admission logs. All data will be entered and stored in REDCap (Research Electronic Data Capture) a HIPAA compliant web-based application.  Although we anticipate all electronic data entry, any paper forms will be kept securely in a locked file cabinet after they are entered into REDCap.  All subjects will be assigned a unique study ID and will be not be referred to by name on study forms (with the exception of the Contact Form). After the child enrolls and completes the in-hospital study requirements (interview, sample collection), the research team will not need to have further contact with the participant while they are in the hospital unless the family has questions. One unlikely exception is if the child remains in the hospital for 21 days. In this case we would collect a nasal swab from the child on day #21 of the hospitalization. For the 1-week post discharge call, we will collect at the time of enrollment participant's contact information with phone numbers and preferred times for calling. Otherwise all other contact with the family will be done via the Coordinating Center.

At each site the biological specimens will be stored in a in a freezer is a secured room.  Each specimen will be labeled with the study ID.  Only study personnel will have access to the personal information linked with this ID.  Only personnel at the EMNet Coordinating Center and the laboratories receiving specimens for testing (Baylor College of Medicine and University of Arizona) will have the codes linking the site numbers and the participating sites.

Q: Investigators are required to obtain only the minimum data necessary to achieve the research goals. Please justify why the data you are obtaining is the minimum necessary.
A: This study is a longitudinal cohort study and as a result, we need to collect many pieces of private information to be able to follow-up with participants over the subsequent years and for sub group-analyses (e.g. by sex or race/ethnicity). We will including name, address, phone numbers, date of birth, gender, race/ethnicity.  We will collect social security number for parents who want to be paid.  Parents may participate if they do not want to provide SSN; however, they cannot be paid for their participation.

Q: Describe where data will be kept, how it will be secured and who will have access to the data.  If links to identifiers are used, please describe the coding mechanism, whether the code is derived from subject information, and how and where the mechanisms for re-identification will be protected and maintained.
A: All study data will be entered and stored in REDCap (Research Electronic Data Capture) a HIPAA compliant web-based application featuring audit trails for tracking data manipulation and export procedures. This application will be hosted by Partners HealthCare Systems (PHS).  PHS has all necessary physical and operational securities in place to meet or exceed Federal and State security and privacy regulations. PHS restricts, monitors, and controls access to systems by authorized personnel who additionally have signed confidentiality and ethical pledges to safeguard data (a condition of employment with PHS) and have performed training in protecting Human Subject data.

Once consented, study personnel will assign the study participant with a unique study identification number or study ID, which is the principal method to identify study participants and their biological specimens.  Each study ID is comprised of a 3-digit site number and a 3-digit individual study participant number.  Only study personnel will have access to the personal information linked with this ID.  Only study personnel at the EMNet Coordinating Center and the other two laboratories receiving biological specimens (the Baylor College of Medicine and the University of Arizona) will have the codes linking the site numbers and the participating sites. The REDCap software ensures that duplicate IDs cannot be created and that all data entered in to the application are associated with a unique ID.

Q: Provide a plan to protect the identifiers from improper use and disclosure.
A: Only study personnel will have access to the personal information linked with this ID.  Only study personnel at the EMNet Coordinating Center and the other two laboratories receiving biological specimens (the Baylor College of Medicine and the University of Arizona) will have the codes linking the site numbers and the participating sites.  Unique identifiers will not be stored in the final database that will be used for analytic purposes. Information such as age, sex, and race will be collected in order to examine the prevalence of bronchiolitis among demographic subgroups. This information will help to establish efforts to improve bronchiolitis care in previously or newly identified high-risk subgroups.  In REDCap all personal identifiers can be labeled as such so that it is possible to export data (and data dictionaries) without any identifying information and also restrict the capability of performing such exports to certain users only.

 Q: Provide a plan for destroying the identifiers at the earliest opportunity consistent with the conduct of the research or provide a health or research justification for retaining the identifiers. For protocols that may be subject to future continuing and secondary data analysis, the IRB highly recommends providing justification for not destroying identifiers permanently.
A: Upon completion of the study, electronic data will be retained by the EMNet Coordinating Center at Massachusetts General Hospital.  Electronic files will be password-protected.  Once the site personnel have entered any data they may have collected on paper sheets into the electronic file, have answered all queries, successfully sent the information to the EMNet Coordinating Center, and the site monitor has signed off on the site, the site PI will be able to destroy the records. However, the existence of any paper forms will be rare since all data will be entered directly in to the REDCap database.

Q: Is there a possibility of clinically significant incidental findings being discovered during research procedure?  Incidental findings may include discovery of unexpected genetic mutations, abnormal results following an MRI of a healthy control, or indications of subject depression following review of quality of life assessments.  Please describe any of potential incidental findings that may result
A: We may identify an abnormal blood level form the complete blood count, specific IgE level, or total IgE. Low levels of 25(OH)D are somewhat expected and therefore have a detailed action plan and are not considered incidental for the purposes of this application.

Q: Outline the plan for addressing incidental findings (i.e. contacting the subject’s primary care provider, referral, etc.).
A: For clinically relevant abnormal CBC and differential values we will contact both the family and the primary care provider. For abnormal total IgE and specific IgE values, the data are not as clear as compared to abnormal CBC and differential values. As a result, the overall study PI, Dr Carlos Camargo, will use the positive predictive values for specific IgE and the food tolerance information we collect from the age 12 month interview to determine the best plan of action for the participants on a case by case basis. Dr Camargo does not want to either unduly alarm any of the families or more importantly, increase the possibility of allergies, by having the families completely avoid a food to which the child has already showed some tolerance.

Q: Dissemination of Research Results
A: We will send letters to the family and the primary care provider listing the results of the 25(OH)D testing and the viruses identified from the hospitalization. These letters will be sent the year following enrollment. Therefore, for abnormal 25(OH)D results, we will recommend to the PCP that the level be repeated.

Q: Regulations require that significant new findings developed during the course of the research, which may relate to the subject's willingness to continue participation, be provided to the subject.  Describe how this requirement will be met.
A: The first outcome in this longitudinal cohort (recurrent wheeze) will occur when the children are age 3 years. If we are able to successfully retain this cohort, we will have had multiple communications with the families. Depending on how the cohort develops and the importance of the finding, we may be able to post the finding on our study website or let the families know over the phone at the next follow-up call or via email.


©2017 EMNet Last Updated:01/21/14 er