Caregiver Early Child Development Training for Preventing Konzo From Toxic Cassava in the Democratic Republic of Congo (DRC)
Phase: NA
Conditions: Malnutrition, Manihot Species Poisoning
Sponsor: Michigan State University

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MICHIGAN STATE UNIVERSITY HUMAN RESEARCH PROTECTION PROGRAM 
• 
Complete this template for new exempt, expedited, or full board studies. 
o Complete Section I for ALL studies (exempt, expedited, full board) 
o Complete Section II ONLY if your study does not qualify for exemption and requires an 
expedited or full board review. Contact the IRB office if you have any questions. 
• 
CLICK™ IRB:  
o Include the template with a New Study Submission. 
o Upload the completed template to the Basic Information SmartForm page, Question 10.  
o When uploading documents to Click (e.g. consent documents, instrument), provide distinct 
file names.  
• 
See the Click Quick Guides and the HRPP Manual for more information, available at hrpp.msu.edu 
 
Study Title: 
Caregiver Early Child Development Training for Preventing Konzo 
from Toxic Cassava in the DR Congo 
MSU IRB approval date: February 14, 2020  
Click Study ID (if known): 
2272 
Sponsor (if applicable): 
NIH 
Sponsor ID (if applicable): 
      
 
Section I. IRB Protocol for All Studies 
Section I is completed for all studies and includes questions to determine whether the study qualifies 
for exemption. Section II is only completed if the study does not qualify for exemption. 
 
1. Hypothesis / Objective / Goals / Aims. 
Briefly describe the study’s hypothesis / objectives / goals / aims.  
Konzo is a neurological disease associated with chronic reliance on poorly processed cyanogenic 
cassava as the main source of food. We found that school age children from konzo areas present 
with poor neurocognition compared to those from nearby non-konzo areas, persisting and 
worsening even 4 years after initial assessment. Our most recent work has extended these 
findings to children as young as a year in age, suggesting that the neurodevelopmental impact 
from cassava cyanide neurotoxicity may begin as soon as children are weaned from breast milk to 
cassava porridge. The “wetting method (WTM)” is a simple and effective method of detoxifying 
cassava flour prior to eating that is being taught to rural women in a clinical-trial study by our 
group in the Democratic Republic of Congo (DRC). The present proposal seeks to combine a 
curriculum of mediational intervention for sensitizing caregivers (MISC) with a WTM training 
program (MISC/WTM). MISC is an early childhood development (ECD) caregiver training program 
previously demonstrated in clinical trials by Boivin and colleagues to improve health, 
neurodevelopmental, and caregiver mental health outcomes in rural Ugandan HIV-affected 
households. Training 66 randomly selected moms from a cohort of 100 on MISC/WTM (while the 
remaining 34 get WTM only) will better sensitize mothers to their children’s development, leading 
to better WTM adherence while providing practical ECD benefits.  
The Aims for this study are: 
 1. To establish the feasibility of adding a biweekly 1-year MISC/WTM training program for 
mothers and their 1 through 4-year-old children, led by peer trainers from the community. MISC 
has been previously implemented for HIV-affected households in Uganda, but not for konzo 
communities in the DRC.  

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2. To document whether better adherence to WTM through MISC will lead to lower household 
flour cassava cyanogenic content and lower urinary thiocyanate (U-SCN) levels in the 
mother/child dyads. We will also test for improved child outcomes on the Fagan Test of Infant 
Intelligence (with automated eye tracking), Mullen Scales of Learning (MSEL), the Early 
Childhood Test of attention (ECVT; eye tracking), and the Color-Object Association Test (COAT). 
Caregiver depression/anxiety and corresponding functionality for activities of daily caregiving 
should also significantly improve.  
 3. To explore whether reductions in cyanogenic exposure from cassava and improved child’s 
neurodevelopmental outcomes are mediated by improvements in caregiver emotional wellbeing 
and caregiving functionality immediately post MISC intervention and at 6-month follow-up. Overall 
Impact. Our DRC/USA partnerships will be the first to implement an evidence-based ECD 
program for at-risk children in the DR Congo, strengthening DRC Ministry of Health efforts to 
prevent konzo. If MISC strengthens the programmatic efforts to prevent konzo, the public health 
impact will be enormous, given the scope of risk in toxic-cassava dependent populations 
throughout central/western Africa. MISC could then also be used for children at ECD risk from 
other infectious diseases. 
 
PUBLIC HEALTH RELEVANCE: Early childhood (1 through 4 yrs) is a period of dramatic 
developmental change that can be seriously compromised by exposure to toxic cyanogenic 
cassava (konzo disease), with potentially great impact throughout central and western sub-Sahara 
Africa in regions dependent on this food staple. In the face of ongoing economic instability and 
nutritional, medical and educational deprivation affecting communities at risk for konzo in the 
Democratic Republic of Congo, no programs exist for sustaining a favorable developmental milieu 
for young children. By establishing the viability of caregiver training intervention to enhance 
functionality among caregivers and improve caregiving quality while preventing konzo, this project 
can benefit neurodevelopment for tens of millions of at-risk children. 
2. Procedures. 
Describe the research procedures that involve obtaining information or biospecimens about a 
living person through interaction or intervention and/or by obtaining their identifiable private 
information or identifiable biospecimens. If subjects will participate in or undergo an intervention, 
fully describe the intervention. If the procedures are longer than 1 page, provide a summary and 
include the full procedures as an attachment. 
Caregiver/child dyads will be randomized (by cluster)  whereby 66 of the 100 households will be 
selected to randomly receive MISC/WTM caregiver training to enhance caregiver mental health 
and functionality and early childhood development. The remaining 34 households will receive 
WTM only (considered the recommended standard of care for the prevention of konzo disease in 
at risk communities). This is in order to see if adding MISC to caregiver training enhances 
adherence to WTM for flour detoxification, corresponding child neurodevelopmental and caregiver 
functionality mental health outcomes – as compared to WTM alone for similar households. To 
maintain concealment of MISC training allocation, the randomization sequence was generated by 
the trial biostatistician located in the USA, who also serves as our clinical methodologist and 
biostatistician for the R01 WTM konzo prevention non-inferiority clinical trial. 
The WTM intervention. The intervention will implement the WTM cassava processing technique in 
participating households. Twenty women with leadership and communication skills have already 
been trained and are implementing WTM in the R01 trial and will do the training for our WTM-only 
households in this R21 study These are mothers who master the WTM technique and have been 
certified as trainers to train and support other small groups of other mothers. They have to been 
able to bring the cassava cyanogenic content to the lowest achievable level, which must be < 10 
ppm as per the WHO recommendations. 
The wetting method to remove cyanogens from cassava flour involves adding dry flour to a bowl 
and marking the level on the inside of the bowl. Water is then added with mixing, the volume of 

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the damp flour initially decreases and then increases as more water is added. No more water is 
added when the level of the wet flour comes up to the mark. The wet flour is then placed in a thin 
layer not greater than 1 cm thick on a mat and allowed to stand for 2 h in the sun or 5 h in the 
shade for the hydrogen cyanide gas to escape. The damp flour is mixed with boiling water to 
make the thick porridge (fufu) which is eaten with pounded, boiled cassava leaves (saka saka) or 
some other food to give it flavor.Colorfully illustrated and durable laminated posters depicting the 
WTM will be distributed to participating households as our previous experience indicate that they 
are kept for more than a year on walls in houses. The WTM approach is our chosen strategy for 
prevention, because it has been repeatedly demonstrated that it helps remove cyanogens in 
poorly processed cassava flour to safe levels, even if the flour is initially very toxic due to poor or 
limited processing. 
Mediational Intervention for Sensitizing Caregivers (MISC) Training Intervention. The MISC/WTM 
trainers will be different from the WTM-only trainers (who will not be certified in MISC). The 
MISC/WTM training will be led by 10 women leaders in the Kahemba community (different than 
the WTM peer or professional trainers) who have already been trained by our Uganda MISC 
consultants in April 2018 and are presently implementing MISC training in Kahemba with 40 
households with younger children as part of a pilot study funded by Michigan State University 
African Alliance Partnership program grant to Professor Boivin (http://aap.isp.msu.edu/research-
funding/grant-program/scaling-grants/). Our two principal Ugandan MISC consultants led the 
MISC intervention teams in both of Boivin’s R34 MH082663 and R01 HD070723 cluster RCT 
studies, and have already conducted a one-week training workshops with our 10 women leaders 
and worked with them in the initial adaptation and implementation of MISC in Kahemba for a one-
week period (May 2018). The Ugandan MISC trainers will continue to train the community leader 
women responsible for MISC training at the Kahemba study site for the present R21 study until 
they are MISC-certified, and continue quality assurance follow-up for fidelity of MISC training in 
Kahemba every six months throughout the R21 study period. In the present pilot study phase, 
training session videos of the ten Kahemba community leader woman MISC trainers conducting 
individual training sessions are planning to upload videotapes of training sessions monthly to a 
highly secured Dropbox. These will be evaluated by our Uganda MISC expert consultants as part 
of a quality assurance evaluation for “fidelity of intervention” in Kinshasa and in Kampala Uganda, 
with the help of a DRC assistant working with us in Kampala and fluent in the local DRC 
languages of Kikongo and Chobwe 
Fidelity of both interventions will be maintained through established methods outlined by the NIH 
Treatment Fidelity Workgroup on consistency in dose, providers, delivery, and receipt of the 
intervention 
Questionnaires will be administered by an experienced interviewer with local language fluency 
and overseen by a study coordinator from the Congo Ministry of Health. The questionnaire seeks 
individual demographic data, occupation (mostly local farming), diet composition (mostly uniform 
cassava), cassava preparation method (including any changes resulting from prior intervention), 
24- hour diet recall (composition, amount and number of meals), smoking history and practice 
(usually negative), prior family episodes of acute cassava cyanide toxicity (severe headache, 
vomiting, convulsions, coma, death), and onset date and course of any symptoms of konzo 
among household members. 
 All caregivers will complete these questionnaire, undergo on-site neurological screening and 
urine SCN and provide blood and urine specimens for the biomarker study at baseline, after six-
months of caregiver training, and at one-year at the conlcusion of the caregiver training period. A 
sample of cassava flour originating from the subject’s household will be collected on the same day 
prior to urine collection. Trained technicians from the Ministry of Health will measure the cyanogen 
content of the cassava flour using the picrate kit as in previous studies or interventions.  
Children will be evaluated with a battery of non-invaisve, performace-based nueorcognitive tests 
at baseline, after six months and at one year after initiating trainings. These evaluations include 
the Modified Fagan Test of Infant Intelligence, the Mullen Scales of Early Learning, the ZEarly 

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CHildhood Vigilance Test. Caregivers will respond to the Home Observation for the Measurement 
of the Environment, the Hopkins Symptoms Checklist-25, and the caregiver functional impairment 
for daily activities. 
 
Other caregiver/child assessments include video-taping of 15 minutes of child/caregiver 
interactions (5 minutes of caregiver feeding of child, washing of child, and work or play with child).  
These videos will be used on tablet as part of the MISC training, but also scored for observed 
mediational interactions in order to assess fidelity of MISC training and quality of caregiving.  
These video will be encrypted and password secured and will not be kept after the study, so as 
not to put the study identity of mothers and their children at risk.  Mothers will consent to these 
videos as part of the informed consent process, and it will be a condition of eligibility for 
enrollment. This procedure with recording and scoring and management of videos was done for 
our Uganda-based clinical studies without adverse incidents or problems, and were clearly an 
important part of this type of caregiver training ECD intervention and assessment in a field-based 
clinical trial. 
 CLICK™ IRB: Upload instruments (e.g. surveys, interview questions, questionnaires, etc.), 
measures, variables, etc. to the Supporting Documents SmartForm page. 
3. Subject Population. 
A. Describe the subject population. 
We will study 100 non-konzo mother/child dyads, and all household children 12 to 48 months of 
age. 34 mother/child pairs will receive 12-months of biweekly home-based personalized training 
sessions with wetting method (WTM) training only to detoxify cassava flour in the prevention of 
konzo, and 66 dyads will receive 12 months of MISC caregiver training to improve early childhood 
development (ECD) combined with WTM. These families represent a homogenous population of 
Congolese people living in the Kahemba district of the Bandundu Province, Democratic Republic 
of Congo (DRC) in southwestern Bandundu province. People in this rural district depend heavily 
on daily cassava root and leaves for food and cash income. A typical population of 100,000 
cultivates about 5000 hectares of cassava per year. Traditional varieties of cassava, which are 
subject to the cassava mosaic virus, yield around 6 tons/hectare per year. Crop losses in the 
1990s ranged from 5% to 95%, thereby resulting in severe food insecurity. Cassava dependency 
resulted in up to 5% of individuals in affected villages developing walking difficulties typical of 
konzo. A substantially larger percentage (estimated up to 10%) has neurological signs and 
symptoms of an earlier stage of konzo in which ambulatory difficulty is not overt. Our recent 
findings suggest that deficits in cognition may also be part of neurological picture. Therefore, this 
is an at-risk population. 
B. Select the age range of subjects (select one): 
 Adults who are 18 or older 
 Specific Age Range:       (Enter Minimum) to       (Enter Maximum) 
C. Study purposefully includes the following subject population(s) (select all that apply): 
 Cognitively impaired adults 
 Minors (children) (view information about the definition of a child) 
 Minors who are wards of the state 
 Pregnant women, fetuses, or neonates 
 Prisoners 
 Students 
D. Study involves (select all that apply): 
 Obtaining, using, studying, or analyzing biospecimens 

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 Funding, support, or other requirement to comply with U.S. Department of Justice regulations 
 Incomplete disclosure or attempted deception of subjects  
 Human subject research that will be conducted in the European Union (EU) or involve EU 
collaborators (Austria, Belgium, Bulgaria, Croatia, Republic of Cyprus, Czech Republic, 
Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Latvia, 
Lithuania, Luxembourg, Malta, Netherlands, Poland, Portugal, Romania, Slovakia, Slovenia, 
Spain, Sweden and the UK - England, Scotland, Wales and Northern Ireland), if selected, 
please list the EU member state(s):  
 Procuring cassava flour samples and urine samples from villagers in Bandundu are routine 
activities for the INRB sub-contractor and the teams from the Congo Ministry of Health. They are 
experienced in collecting, processing, storing and shipping samples. Pre-printed labels with 
unique identification numbers are placed on each sample tube. Cassava flour and urine samples 
and their analysis are performed in the village setting, with results evident to both subject and 
investigator. The significance of the reagent-induced color change (density varying directly with 
SCN concentration) will be explained to the villager as part of the intervention. The SCN content 
and color of the urine sample will be entered into the questionnaire and the sample discarded. In 
the R01 study, additional urine, dry blood spots (DBS), and blood (serum/plasma) samples are 
being individually labeled for laboratory analysis of the different biomarkers (8.12-isop, pep1, 
pep2, and homocitrulline). Therefore, a good procedure is already in place in terms of securing 
the custody chain for handling specimens of this sort for our R21. Again, this information will be 
gathered before, at 6- and at 12-months following MISC training in coordination with the R01 
study, and be made available for the proposed R21 study for co-enrolled caregivers and the very 
young study children in their households. In the present R21 study, urine samples are individually 
labeled with their unique ID numbers, flash-frozen or in a dry-ice refrigerated container as needed 
and transported to INRB Kinshasa. A transmittal slip (multiple copies) accompanies each sample, 
and a copy is retained in the study office chain-of-custody (COC) procedures ensure security of 
transportation from the origin (Bandundu villages) to destination (INRB, Kinshasa). The local study 
coordinator fills out a three-part check-in sheet using the sample tracking codes. The study 
number in combination with the sample number is identified as the key field, and all the 
information specific to the sample is referenced by the codes. The check-in sheet must be 
complete in order to track biological samples. After the check-in sheet is completed, the first copy 
is used to enter the information into the Sample Tracking Database and then filed with the 
laboratory liaison. The second copy is given to the Kinshasa project leader. The sample custodian 
compares each sample with its corresponding 
COC, then signs and dates the COC showing receipt at the warehouse. A three-part check-out 
sheet is used to enter data into the Sample Tracking Database and track sample location. 
Comparable COC procedures will be used for the secure mailing of samples from the DRC to the 
USA, for delivery to MSU (R21) and OHSU (R01). Unique sample ID numbers will be used by the 
OHSU study coordinators to register the samples upon arrival, with crosschecking of each sample 
on a listing provided by the Kinshasa dispatcher. 
Data are being entered into the secure database immediately after each batch of samples has 
been analyzed. 
 CLICK IRB: Upload the debriefing script, document, etc. to the Consent Forms and Recruitment 
Materials SmartForm page, Question 1. 
4. Estimated Study Duration. 
Provide the time estimated to complete all human subject research, including analysis of the 
subjects’ identifiable private information. 
3 years 
5. Reasonably Foreseeable Risks. 

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A. There are (select one of the following): 
 
 No reasonably foreseeable risks to subjects 
 Reasonably foreseeable risks to subjects 
B. Explain the selection. If you selected that there are reasonably foreseeable risks to subjects, 
describe the risks, considering physical, psychological, social, legal and economic risks. 
The major risk to enrolled subjects concerns misunderstanding of the purpose of the study, fear 
of the consequences of participating or not participating, stigma arising therefrom, and concern 
regarding study outcomes. Another potential risk is a failure to understand why a medical team is 
focused on prevention of konzo and cannot offer a treatment or cure for extant disease victims. 
Based on our prior experience in our preliminary research described in the research plan 
(Kashala-Abotnes et al., 2017) as well as in the Uganda MISC clinical trial studies, we have 
documented no adverse effects from neurodevelopmental testing of the younger children. The 
same is true for the caregiver functionality and depression/anxiety (mental health) 
questionnaires, and HOME evaluations specific to this proposal. 
C. If you selected that there are reasonably foreseeable risks, describe the procedures for 
protecting against or minimizing potential risks and provide an assessment of their likely 
effectiveness. 
Risks relating to misunderstanding will be minimized by the process of consenting as described 
above, with sequential explanations provided to tribal leaders, villager groups, and individual 
subjects. We have protocols in place to protect human subjects from the assessments we’re 
using and report adverse events from the R01 study which this R21 study is occurring within its 
jurisdiction. Data confidentiality will be ensured by the procedures explained above, including the 
use of unique numbers to identify enrollees, and the secure storage of identifying personal 
biodata (including a photograph) on the front page of the questionnaire that has been separated 
from other data fields on the questionnaire. These procedures are expected to be effective since 
the INRB sub-contractor is experienced in the conduct of human research studies to 
international standards. Any subject with a condition that requires medical attention will be 
referred to the general hospital serving the area of interest. 
6. 
Conflict of Interest. 
Do any investigators or research staff have a financial interest related to the 
research that has not otherwise been disclosed elsewhere in this submission? 
 No 
 Yes 
7. 
Exemption Criteria.  
 Not Applicable  
A study may qualify for exemption when the only involvement of human subjects will be in one or 
more of the following categories (please view full exemption category / description here: 
https://hrpp.msu.edu/help/required/exempt-categories.html).  (If the study does not qualify for 
the exemption criteria, do not complete this question and proceed to Section II.) 
A. Exemption Categories.  
1. Select the category(ies) applicable to the study if the only involvement of human 
subjects in this study will be in one or more of the categories. Studies involving 
prisoners cannot be exempt UNLESS the research is aimed at involving a broader 
subject population that only incidentally includes prisoners If your study is subject to 
U.S. Department of Justice requirements, do not complete this section; complete 7A2 
below. 
 Exempt 1. Research conducted in established or commonly accepted educational settings, 
involving normal educational practices that are not likely to adversely impact students' 
opportunity to learn required educational content or the assessment of educators who provide 

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instruction. IF YOU SELECTED THIS CATEGORY, EXPLAIN WHY THE RESEARCH WILL 
NOT LIKELY ADVERSELY IMPACT STUDENTS’ OPPORTUNITY TO LEARN REQUIRED 
EDUCATIONAL CONTENT OR THE ASSESSEMENT OF EDUCATORS WHO PROVIDE 
INSTRUCTION. 
       
 Exempt 2. Research that only includes interactions involving educational tests (cognitive, 
diagnostic, aptitude, achievement), survey procedures, interview procedures, or observation of 
public behavior. IF YOU SELECTED THIS CATEGORY, SELECT THE APPROPRIATE 
OPTION(S) BELOW. 
 
 (i) Information obtained is recorded by investigator in manner that identity of subjects 
cannot readily be ascertained, directly or through identifiers linked to subjects 
 
 (ii) Any disclosure of subjects' responses outside research would not reasonably place 
subjects at risk of criminal or civil liability or be damaging to subjects' financial standing, 
employability, educational advancement, or reputation. 
 
 (iii) LIMITED IRB REVIEW REQUIRED. Information obtained is recorded by investigator in 
manner that identity of subjects can readily be ascertained, directly or through identifiers 
linked to subjects, and responses could reasonable place subjects at risk of criminal or civil 
liability or be damaging to the subjects' financial standing, employability, educational 
advancement, or reputation (LIMITED IRB REVIEW IS REQUIRED; YOU MUST ALSO 
COMPLETE QUESTION 7E TO DESCRIBE PRIVACY AND CONFIDENTIALITY 
SAFEGUARDS.) 
 Exempt 3. Research involving benign behavioral interventions in conjunction with the collection 
of information from an adult subject through verbal or written responses (including data entry) or 
audiovisual recording if the subject prospectively agrees to the intervention and information 
collection. IF YOU SELECTED THIS CATEGORY, SELECT THE APPROPRIATE OPTION(S) 
BELOW.   
 
 (i) Information obtained is recorded by investigator in manner that identity of subjects 
cannot readily be ascertained, directly or through identifiers linked to subjects. 
 
 (ii) Any disclosure of subjects' responses outside research would not reasonably place 
subjects at risk of criminal or civil liability or be damaging to subjects' financial standing, 
employability, educational advancement, or reputation 
 
 (iii) LIMITED IRB REVIEW REQUIRED. Information obtained is recorded by investigator in 
manner that identity of subjects can readily be ascertained, directly or through identifiers 
linked to subjects, and responses could reasonable place subjects at risk of criminal or civil 
liability or be damaging to subjects' financial standing, employability, educational 
advancement, or reputation (LIMITED IRB REVIEW IS REQUIRED; YOU MUST ALSO 
COMPLETE QUESTIONS 7E TO DESCRIBE PRIVACY AND CONFIDENTIALITY 
SAFEGUARDS.) 
 Exempt 4. Secondary research uses of identifiable private information or identifiable 
biospecimens. IF YOU SELECTED THIS CATEGORY, SELECT THE APPROPRIATE 
OPTION(S) BELOW.   
 
 Identifiable private information or identifiable biospecimens are publicly available. 
 
 Information, which may include information about biospecimens, is recorded by the 
investigator in such a manner that the identity of the human subjects cannot readily be 
ascertained directly or through identifiers linked to the subjects, the investigator does not 
contact the subjects, and the investigator will not re-identify subjects. IF YOU SELECTED 
THIS CATEGORY, CONFIRM THE FOLLOWING: 
  
 
 Investigator and research team will not contact the subjects 
 Investigator and research team will not re-identify the subjects 
 
 The research involves only information collection and analysis involving the investigator's 
use of identifiable health information when that use is regulated under the Health Insurance 
Portability and Accountability Act (HIPAA) 45 CFR parts 160 and 164. 

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 The research is conducted by, or on behalf of, a Federal department or agency using 
government-generated or government-collected information obtained for nonresearch 
activities, if the research generates identifiable private information that is or will be 
maintained on information technology that is subject to and in compliance with specific 
federal privacy standards. 
 Exempt 5. Federal demonstration projects. 
 Exempt 6. Taste and food quality evaluation and consumer acceptance studies. 
 Exempt 97. ONLY applicable to research NOT FUNDED by a federal department or agency: 
Research involving the study of previously collected identifiable data (please view additional 
exclusions before selecting this category). 
 By checking the boxes below, you are confirming that the study will not include any of the 
following exclusions for the study’s duration: 
 Federal funding or federal training grants 
 FDA regulated 
 Sponsor or other contractual restrictions 
 Clinical interventions (including clinical behavioral interventions) 
 Receipt of an NIH issued certificate of confidentiality to protect identifiable research data 
 Multi-site collaborative research study where another institution plans to rely or is relying 
upon MSU’s IRB review 
 Exempt 98. ONLY applicable to research NOT FUNDED by a federal department or agency: 
Prospective data collection with adults through verbal or written responses involving a benign 
intervention (please view additional exclusions before selecting this category). 
 By checking the boxes below, you are confirming that the study will not include any of the 
following exclusions for the study’s duration: 
 Federal funding or federal training grants 
 FDA regulated 
 Sponsor or other contractual restrictions 
 Clinical interventions (including clinical behavioral interventions) 
 Receipt of an NIH issued certificate of confidentiality to protect identifiable research data 
 Multi-site collaborative research study where another institution plans to rely or is relying 
upon MSU’s IRB review  
 Children as research subjects 
2. DEPARTMENT OF JUSTICE Exemption Categories. Complete this section ONLY if the 
research is subject to Department of Justice requirements. 
i. Select the category(ies) applicable to the study if the only involvement of human 
subjects in this study will be in one or more of the categories. Studies involving 
prisoners cannot be exempt. 
 Exempt 1. Research conducted in established or commonly accepted educational settings, 
involving normal educational practices. 
 Exempt 2. Educational tests, survey procedures, interview procedures, observation of public 
behavior unless data is recorded in a manner such that subjects are identifiable and the 
responses could reasonably place the subjects at risk of criminal or civil liability or be damaging 
to the subjects’ financial standing, employability, or reputation (research cannot involve children, 
except for educational tests or observation of public behavior where the investigator does not 
interact with the child). 
 Exempt 3. Educational tests, survey procedures, interview procedures, or observation of public 
behavior not otherwise exempt that involves public officials or federal statute. 
 Exempt 4. Collection or study of existing data, documents, records, pathological specimens, or 
diagnostic specimens if publicly available or information is recorded by investigator in a manner 
that subjects cannot be identified.  
 Exempt 5. Federal demonstration projects. 
 Exempt 6. Taste and food quality evaluation and consumer acceptance studies. 

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ii. Explain why the study presents minimal risk to subjects. 
 
       
B. By checking the boxes below, you are confirming that the following are true and will remain true 
for the study’s duration: 
  Selection of subjects is equitable (considering the purposes of the research, setting in which 
research will be conducted, any vulnerable populations). 
  If there is recording of identifiable information, there are adequate provisions to maintain the 
confidentiality of the data. 
  There are adequate provisions to maintain the privacy interests of subjects. 
  Safeguards are or will be put in place to protect against any coercion or undue influence if you 
or members of your study team are or may be associated with the subjects at any point in the 
study (e.g. students, employees, colleagues, patients). 
C. Consent  
i. There will be a consent process for the study’s duration that will disclose information such as that 
the activity involves research, a description of the procedures, that participation is voluntary and 
withdrawal is without penalty, and the name and contact information for the researcher (select 
appropriate option below): 
 For All Subjects  
 For Some Subjects 
 For None of the Subjects (consent will not be obtained) 
CLICK IRB: Upload the consent document to the Consent Forms and Recruitment Materials 
SmartForm page. 
ii. Please explain your selection.  
      
D. Please acknowledge that you may not begin the research at non-MSU institutions (regardless of 
engagement), until you receive the appropriate approvals/permissions from the sites (e.g. IRB 
review/exempt determination from non-MSU sites, data use or research agreements, other 
regulatory approvals). An MSU exempt determination does not provide approval/permission for a 
non-MSU site, including sites with reliance agreements with MSU. Please note that non-MSU 
sites may have requirements that differ from MSU for exempt research. Note that this also applies 
to sites added after the MSU exempt determination. 
 Acknowledged 
E. LIMITED IRB REVIEW. If the exemption(s) require limited IRB review (if you selected Exemption 
2(iii) or 3(i)(C) in Question 7A), complete questions 1 and 2 to describe privacy and confidentiality. 
1. Privacy of Subjects. 
 How will subjects’ privacy be protected? Consider the number of individuals interacting with the 
subject or subject’s records, location of consent process and study, presence of individuals not 
associated with the study, sensitivity of the research. 
       
2. Confidentiality of Data. 
i. Select the appropriate option:  
 
 Identifying or coded information will not be stored with the information and/or biospecimen(s) 
 Identifying or coded information will be stored with the information and/or biospecimen(s) 

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ii. Please explain your selection. If you are storing identifying or coded information with the 
information and/or biospecimen(s), explain why identifiable or coded information and/or 
biospecimen(s) needs to be maintained and how long it will be necessary to maintain it.  
       
iii. Describe the procedures and safeguards you will use to secure the information and/or 
biospecimen(s), including during transport of information and/or biospecimen(s). 
 
      
 
 
 
 
 
Other Click IRB Documents to Upload As Appropriate 
(Applicable to All Studies) 
 
• 
Upload this completed protocol to the Basic Information SmartForm page, Question 10. 
• 
Upload any funding materials not accessible in Kuali Coeus in the Supporting Documents 
SmartForm page. 
• 
Upload the HRP-537 - Template - Use of Protected Health Information Application to the 
MSU Additional Study Information SmartForm page. 
• 
Upload the HRP-538 - Template - MSU Authorization to Use or Disclose Health Information 
for Researchers to the MSU Additional Study Information SmartForm page. 
 
 
 
 
 
IF THE STUDY MAY QUALIFY FOR AN EXEMPTION  
(INCLUDING THOSE THAT MAY REQUIRE LIMITED IRB REVIEW),  
STOP HERE AND DO NOT COMPLETE SECTION II.  
 
CONTINUE ONLY IF THE STUDY  
DOES NOT QUALIFY FOR AN EXEMPTION.  
COMPLETE QUESTIONS 8-24 FOR AN EXPEDITED OR FULL BOARD 
STUDY. 
 
 

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Section II. Additional Questions for an Expedited or Full Board Study 
Not all questions or sections are applicable to every study. If the question or section is not applicable, 
check the “Not Applicable” box. All other questions are required. 
8. Expedited Categories. 
A. Please select the Expedited category(ies) and sub-categories as applicable to the study if the only 
involvement of human subjects in this study will be in one or more of the categories. If the study 
involves more than minimal risk or none apply, select “The study involves more than minimal risk 
OR none of the expedited category(ies) apply.” 
 
 
The study involves more than minimal risk OR none of the expedited categories apply. IF 
THIS OPTION IS SELECTED, DO NOT SELECT ANY OF THE EXPEDITED CATEGORY(IES). 
 
 
Expedited 1. Clinical studies of drugs and medical devices only when condition (a) or (b) is met. IF 
YOU SELECTED THIS CATEGORY, SELECT THE APPROPRIATE OPTION(S) BELOW. 
  
 
(a) Research on drugs for which an investigational new drug application (21 CFR Part 312) 
is not required. (Note: Research on marketed drugs that significantly increases the risks or 
decreases the acceptability of the risks associated with the use of the product is not eligible 
for expedited review.) 
  
 
(b) Research on medical devices for which (i) an investigational device exemption 
application (21 CFR Part 812) is not required; or (ii) the medical device is cleared/approved 
for marketing and the medical device is being used in accordance with its cleared/approved 
labeling. 
 
 
Expedited 2. Collection of blood samples by finger stick, heel stick, ear stick, or venipuncture. IF 
YOU SELECTED THIS CATEGORY, SELECT THE APPROPRIATE OPTION(S) BELOW. 
  
 
(a) from healthy, nonpregnant adults who weigh at least 110 pounds. For these subjects, the 
amounts drawn may not exceed 550 ml in an 8 week period and collection may not occur 
more frequently than 2 times per week; or 
  
 
(b) from other adults and children [2], considering the age, weight, and health of the 
subjects, the collection procedure, the amount of blood to be collected, and the frequency 
with which it will be collected. For these subjects, the amount drawn may not exceed the 
lesser of 50 ml or 3 ml per kg in an 8 week period and collection may not occur more 
frequently than 2 times per week 
 
 
Expedited 3. Prospective collection of biological specimens for research purposes by noninvasive 
means. 
 
 
Expedited 4. Collection of data through noninvasive procedures (not involving general anesthesia 
or sedation) routinely employed in clinical practice, excluding procedures involving x-rays or 
microwaves. Where medical devices are employed, they must be cleared/approved for marketing. 
(Studies intended to evaluate the safety and effectiveness of the medical device are not generally 
eligible for expedited review, including studies of cleared medical devices for new indications.) 
 
 
Expedited 5. Research involving materials (data, documents, records, or specimens) that have 
been collected, or will be collected solely for nonresearch purposes (such as medical treatment or 
diagnosis).  
 
 
Expedited 6. Collection of data from voice, video, digital, or image recordings made for research 
purposes. 
 
 
Expedited 7. Research on individual or group characteristics or behavior (including, but not limited 
to, research on perception, cognition, motivation, identity, language, communication, cultural beliefs 
or practices, and social behavior) or research employing survey, interview, oral history, focus group, 
program evaluation, human factors evaluation, or quality assurance methodologies.  
B. For Studies Regulated by the U.S. Food and Drug Administration or the U.S. Department of Justice. 
If you selected an expedited category, explain why the study presents minimal risk to subjects. 
       

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9. More than Minimal Risk Research. Complete the following question if you selected “The study 
involves more than minimal risk OR none of the expedited categories apply” in Question 8A 
(Expedited Categories). 
A. Describe the relevant prior experience and gaps in current knowledge, relevant preliminary data, if 
any, and the scholarly background for, and significance of, the research based on existing 
literature and how it will add to existing knowledge. 
Many chronic degenerative diseases, including those affecting the nervous system, are expected 
to have etiologies that result from yet-to-be-understood environmental exposures. Biomarkers of 
disease as well as pathways involved in their pathogenesis have yet to be uncovered. The 
propose study will shed light on the specifics of cyanide/cyanate-associated neurodegeneration. 
Our research findings as applied to early childhood development in konzo at-risk households will 
provide a strong basis for bench studies to reveal pathways involved in the death of motor 
neurons under exposure to cyanogenic compounds and propose drug candidates to either prevent 
or reverse symptoms that would arise from such exposure. For the study subjects, knowledge of 
how to prevent konzo (WTM), how to enrich the early learning environment of their children 
(MISC), with concurrent ECD-based understanding of how to promote brain development, greatly 
outweighs the minimal risks of bruising and/or adverse emotional effects for out maternal 
evaluations. For the community, the public health professionals, and the governments of countries 
with a cassava-dominated diet, this study is expected to provide information of markers that can 
be used to monitor risk associated with dietary dependency on poorly processed bitter cassava. In 
the present R21 proposal, we also hope to lay the foundation for partnership that can continue to 
build capacity for the implementation of caregiver training in practical strategies to protect and 
enrich the learning and neurodevelopmental environment of their at-risk very young children. The 
findings of the proposed studies are of high translational potential as they may be applicable to all 
manner of children at risk in the DRC neurodevelopmentally from poor or toxic nutrition, chronic 
and infectious disease that puts the caregiver and/or child at significant risk. Finally, our findings 
will help understand the type of risks and markers of neurological disease in very young children, 
associated with cyanogenic exposure that may arise under other circumstances such as exposure 
to cyanogenic compounds under environmental contamination during mining operations as occur 
throughout the DRC. MISC may provide practical tools for moms with which to intervene on behalf 
of their disabled children, while encouraging their mental health and functionality as it relates to 
caregiving quality. 
B. Sample Size. 
i. Total number of subjects who will be approached (including screen failures, controls and subject 
withdrawals) to reach enrollment numbers for the lifetime of the study at this investigator’s sites. 
 140 households 
ii. Total number of subjects who will be enrolled in the study at this investigator’s site. 
 This study will enroll 100 households without a konzo individual (based on neurological exam) in 
the family and where the mother of one of more children under 4 yrs of age is the principal food 
preparer. 
iii. Describe the statistical justification or rationale for the proposed sample size. Considerations for 
sample size may include the acceptable level of significance, power of the study, expected effect 
size, underlying event rate in the population, standard deviation in the population, saturation of 
themes, and/or have a theoretical basis. 
  
This exploratory developmental R21 project aims to generate hypotheses for subsequent formal 
testing in an R01-supported larger trial. Therefore present sample size considerations are based 

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on project timeline and resources. With n=66 in MISC+WTM arm and n=34 in WTM only arm. 
Based on our clinical studies with a biweekly MISC caregiver training with mothers with HIV in 
rural eastern Uganda, we expect an over 90% retention rate for the full year.  With this retention 
rate, the unadjusted effect size of 0.60 is detectable as statistically significant with power of 0.80 
and 0.05 level of significance in two-tailed tests, that is differences between trial arms of 0.6 of the 
standard deviation or greater will be captured with statistical significance. For the main trial arm 
effect (differences between arms over time) from two repeated measures at 6 and 12 months with 
the planned covariance adjustment for baseline, the adjusted standard deviation is smaller than 
the unadjusted due to the reduction in error variance. Assuming correlation of 0.4 between pairs of 
repeated measures seen in past testing of MISC, the adjusted detectable effect size is 0.44. This 
effect size is consistent with past testing of MISC in HIV-affected households that produced effect 
sizes ranging from 0.35 to 0.53, and is below the threshold of 1/2 of the standard deviation for 
clinical significance. Thus any meaningful differences between arms will be captured with the 
proposed sample size. If the differences between trial arms correspond to the adjusted effect size 
smaller than 0.44, the effect size will be estimated in this study and used to power future clinical 
trial studies.  
10. Minimal Risk Research. Complete the following question if you selected an expedited category in 
Question 8A. 
A. Briefly describe the background for conducting the research. (1-2 sentences) 
      
B. Sample Size. 
i. Provide an estimated sample size for the lifetime of the study at this investigator’s sites. 
   
ii. Describe the basis for that estimate. 
      
11. Benefits.  
Describe any potential direct benefit(s) to subjects in this study, if any and the importance of the 
knowledge that may reasonably be expected to result. Within the description, do not include 
payment to subjects as a benefit. 
The proposed research is designed to evaluate the value-added benefit of embedding WTM 
caregiver training within a more comprehensive MISC ECD program so as to better prevent the 
toxic effects of cassava on the developing brain in very young children. Also, we hope to identify 
key biomarkers of early childhood neurodevelopment that can be utilized to monitor the health 
risks associated with the consumption of poorly processed cassava. Finally, for the present 
mothers in konzo-affected communities in the DRC, we hope to see whether MISC can provide 
the same mental health benefits and the caregiving functionality in activities of daily living, and 
diminished depression and anxiety mental health benefits as evidenced in its application with 
Ugandan mothers with HIV. Throughout the recruitment process and the course of the study, 
villagers will learn that they need to correctly process cassava prior to its consumption and also, 
diversify their diet. This type of information is already given to the population by the PRONANUT 
team and will be just emphasized during interviews with villagers. The long-term benefit for 
healthy subjects is a reduced risk for konzo. For individuals at risk for konzo (mothers and even 
very young children; Kashala-Abotnes et al., 2017), the long-term benefit is a reduced risk for 
advancement of spastic paraparesis and associated neurodevelopmental disability. Reduced 
exposure of pregnant women and children to cyanogens should also promote brain development 
by reducing the risk for thiocyanate-induced hypothyroidism and/or cyanate-induced neurotoxicity. 

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Prevention of the risk of spastic paraparesis (konzo) in children and adults reduces chances of 
lifelong disability and societal stigma. This greatly outweighs the minimal risk of bruising or 
infection following phlebotomy. Automated eye tracking data will be gathered for two of the 
neurodevelopmental assessments (Fagan Test of Infant Intelligence working memory for human 
faces; Early Childhood Vigilance Test of attention). These data can be explored and evaluated for 
what they can provide in terms of additional neuro-ophthalmological and eye motility indicators of 
pre-clinical or early onset konzo disease in very young children. This has not been done before 
with pediatric konzo disease, and is a highly innovative feature of the present study proposal. 
12. Screening, Recruitment, and Determining Eligibility.  
A. Describe the criteria for who will be included or excluded from the study, including how subjects 
will be screened for eligibility 
 The proposed study will enroll 100 households from villages not presently enrolled in the R01 
study. Eligible households must have at least one child less than 4 years of age, and the biological 
mother of the child must be the primary caregiver and food provider for the child.Eligible 
households may NOT have an older child or other family member already affected by konzo, thus 
the results will be generalizable to a broader population.  Enrollment and randomization will occur 
at the village level.  After 100 households with children 1-4 years of age complete baseline 
assessments, 66 of them will be randomly selected to undergo individualized MISC+WTM training 
sessions by peers trained in the MISC+WTM curriculum, who will come to their homes for a 1 to 2 
hr. session on a biweekly basis. 
Exclusion Criteria.  At pre- study medical examination we will exclude children with a medical 
history of serious birth complications, severe malnutrition, bacterial meningitis, encephalitis, 
cerebral malaria, or other known brain injury or disorder requiring hospitalization. Also children 
with seizure or other neurological disability will be excluded. Serious CNS neurodisabilities would 
prevent such children from completing the MISC intervention, and possibly significant portions of 
the neuropsychological test battery.  
B. Describe how subjects will be identified and recruited, including who will perform the recruitment.  
 
This study will enroll 100 households where the mother is the principal caregiver and food 
preparer for one or more children from 1 to 4 yrs of age.  If multiple biological children for a study 
mother are in that age range, they will all be enrolled and assigned as a household to the same 
caregiver training trial arm (either MISC/WTM or WTM only). However, the mother cannot be 
diagnosed with konzo following a full neurological exam at study enrollment, so that she is able to 
full implement MISC and/or WTM training. Randomization occurs by geographic location (i.e. 
village) rather than individually to minimize the likelihood of contamination and diffusion effects 
within a community. Our MISC biweekly year-long caregiver training with rural Ugandan HIV 
mothers using MISC training resulted in a pre- to post-year retention rate of over 90% in our 
dyads, and we anticipate at least that retention rate given the fact that our mothers and children 
are not affected by HIV and those health and motivational issues. 
 
We will randomly select our eligible households from a health zone census already established by 
the PRONANUT for Kahemba district in preparation for the R01 peer- versus professional-led 
non-inferiority clinical trial for teaching small groups of mother the use of WTM to detoxify their 
cassava flour before eating.  The present study will stratify its sample selection so that half of the 
participating households will be from peer- and half will be from professional-led health zones.  Ho 
Also, the mothers of the study children are responsible day-to-day for cassava flour preparation.  
Mother and child have no prior history of severe medical condition or brain infection, accident, or 
injury which may preclude the ability to learn WTM and/or MISC and benefit from it in terms of 
functionality (maternal) or neurodevelopmental (child) outcomes. Once enrolled, they will be 

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cluster randomized to either the MISC/WTM or WTM-only peer-led training standard of care. 
Randomization will occur by geographic location (i.e. village) rather than individually to minimize 
the likelihood of “spillover” (contamination and diffusion) effects within a community, whereby 
caregivers receiving training by a specialist provider might share aspects of their experience with 
caregivers receiving training from a peer-provider. Therefore villages participating in this study will 
be randomly assigned to peer- versus specialist-led group training intervention (randomized 
cluster technique). To maintain concealment of allocation, the randomization sequence will be 
generated by the trial biostatistician who is a full professor at MSU and very experienced at the 
clinical methodology and the statistical assessment of our study outcomes. She is the clinical 
methodologist and biostatistician for the konzo WTM non-inferiority R01 study, and will serve the 
same role in this study. Child neurodevelopmental and urinary thiocyanate and quality of home 
environment and evaluation of observed MISC interactions using the caregiving videos will be 
done by research assistants blinded to caregiver training intervention arm in the present study. 
C. Identify materials that will be used to recruit subjects (select all that apply): 
 None 
 Letter, email, flyer, postcards, CD, DVD 
 Newspaper, television, or radio advertisements  
 Use of websites or Apps (e.g. Facebook, ResearchMatch) 
 Other, describe if other is selected: 
       
 CLICK IRB: Upload the recruitment materials to the Consent Forms and Recruitment Materials 
SmartForm page, Question 2. 
D. The study team will obtain for the purpose of screening, recruiting, or 
determining the eligibility of prospective subjects (please select the 
appropriate option(s)): 
 Not Applicable 
 
 Information through oral or written communication with the prospective subject or legally 
authorized representative. Before the information is obtained for the purpose of screening, 
recruiting, or determining eligibility, consent: 
 will be obtained. 
 will not be obtained. 
Please describe screening consent procedures in Question 13. 
 
 Identifiable private information or identifiable biospecimens by accessing records or stored 
identifiable biospecimens. Before the information is obtained for the purpose of screening, 
recruiting, or determining eligibility, consent: 
 will be obtained. 
 will not be obtained. 
Please describe screening consent procedures in Question 13. 
Note: The revised Common Rule permits an exception from informed consent for screening, 
recruiting, or determining eligibility when certain criteria are met; this exception does not apply 
to studies subject to the Pre-2018 Common Rule Requirements and/or studies regulated by 
the U.S. Food and Drug Administration (FDA). 
1. Please explain your selection(s). 
 Participation also requires receiving information on how to process cassava so that it is safe to 
eat. If and when the village tribal leader grants permission, groups of villagers will be invited to 
assemble and learn why the team has visited their village. The Kinshasa study team will repeat 
to the villagers the information previously provided to the tribal leaders. They will be 
encouraged to ask questions to which answers will be provided. Konzo will be familiar to the 
villagers, but they may not understand the causal connection between the consumption of 
cassava and the induction of walking difficulty. In particular, since cassava is a staple that 
provides a major source of nourishment that keeps them alive, there may be disbelief that a 
causal connection with disease could be possible. Other explanations for walking difficulties 
may be offered by the villagers, including punishment for undefined wrongdoing, a curse 
placed upon villagers by another tribal group, or the result of a natural event such as a flood or 

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a drought. Explanation that studies have shown that other people both near and far also 
develop “tied legs” if they do not wash their cassava roots for a sufficient period of time usually 
overcome doubts and focus attention on the principal cause of konzo. Great care must be 
taken to explain that cassava is an important and healthy food for the community provided it is 
properly prepared for human consumption. Since women of the village have major 
responsibility for food preparation and take pride in providing adequate nutrition for their family 
members, optimal food preparation is a subject of considerable interest and pride. Villagers will 
be familiar with the fact that children and women of childbearing age are the most heavily 
affected by konzo (relative to adult men), and it will therefore be logical that women and 
children are subjects of special importance to the study team. 
13. Consent Process. 
A. If the study involves adults, consent will be obtained from (select 
appropriate option(s)): 
 Not Applicable 
 All subjects  
 Some subjects  
 No subjects (consent will not be obtained) 
 CLICK IRB: Upload the consent document, script, etc. (including translations) to the Consent 
Forms and Recruitment Materials SmartForm page, Question 1. 
B. If the study involves children, parental permission will be obtained from 
(select appropriate option(s)):   
 Not Applicable 
 Both parents or guardians (unless one parent is deceased, unknown, incompetent, or not 
reasonably available, or when only one parent has legal responsibility for the care and custody 
of the child) 
 One parent or guardian 
 Will not be obtained 
 CLICK IRB: Upload the parental permission forms to the Consent Forms and Recruitment 
Materials SmartForm page, Question 1. 
C. If the study involves children, child assent will be obtained from (select 
appropriate option):  
 Not Applicable 
 All children 
 Some children 
 Will not be obtained 
 CLICK IRB: Upload the child assent form to the Consent Forms and Recruitment Materials 
SmartForm page, Question 1. 
D. Describe the consent process, including an explanation of your selection(s) above. If the study 
involves screening activities, please describe whether consent will be obtained and if consent will 
not be obtained, explain how the screening data will be used. If only some subjects will provide 
consent, explain who will or will not provide consent. If only some children will provide assent, 
explain which children will and will not provide assent.  
Consenting will be performed by a member of the Kinshasa team on an individual basis after 
subjects have participated in the group meeting. Each subject will be asked to explain the purpose 
of the study: correct answers will be reinforced, and incorrect answers will be corrected with 
further information until the subject has a clear understanding. The subject will be informed they 
are free to accept or decline the invitation to participate and, if they choose to accept, they may 
withdraw at any time without recourse or penalty. Before making a decision whether to accept or 
decline, they will learn that participation in the study means the following: the study will have 

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access to the information being provided, as they provide a sample cassava flour, urine, and 
caregiver mental health/functionality and child neurodevelopment outcomes, for the study each 
time the research team visits the village over the course of the study period; answer some 
questions and provide a urine sample; be willing to learn about the MISC caregiver training 
intervention if chosen for that intervention arm in the study. 
They are being told that their flour and urine samples will help the study team understand how to 
advise them on the best cassava preparation and risk for the disease konzo. They are also being 
informed that information collected from their blood/urine may be used in additional future studies 
of other diseases and their treatments. Participants will be encouraged to ask questions and, if 
necessary, take the necessary time to consider whether to participate or not. As noted in the 
research plan, after the first month of MISC training (under the supervision of experienced and 
Uganda certified MISC trainers at the Kahemba study site), the ten community women leaders 
trained to do the MISC trainers will continue to do bi-weekly personal MISC training sessions in 
the homes of the mothers to whom they have been assigned. One monthly encrypted and 
password protected videotaped MISC training session for each trainer will be uploaded to a 
secured DROPBOX for the remainder of the six-month MISC intervention period. These will be 
evaluated at our assessment center in Kampala Uganda for quality assurance and corrective 
feedback of the MISC training. We have used a similar procedure before for MISC training QA at 
our satellite study sites in rural areas of eastern Uganda, and the process worked well. A separate 
consent to video will be obtained from the mothers before the videotaping of any sessions, and 
the videotape will be available in a DROPBOX site that is only accessible to the trainers and the 
Ugandan MISC supervisors. Co-investigators Drs. Esperance Kashala-Abotnes and Itziar 
Familiar-Lopez, who have oversight for the MISC intervention portion, will also have access. All 
videotapes will be removed from the DROPBOX site and deleted within two weeks following 
evaluation for QA by the Ugandan MISC supervisors. This will all be explained in the separate 
consenting process of the mothers selected for the MISC training session videotaping with a given 
trainer for that month. 
Agreement to participate will be taken if the child makes a clear statement of assent relevant for 
the present study, since all study children are under 7 yrs of age. The consent document will 
explain the purpose of the study, why questions will be asked, why flour and urine information is 
needed to be obtained for the study, the benefits and risks to the subjects, the payment schedule 
and amount, and the possibility of accepting or declining without consequence. There will be a 
clear statement that treatment of the disease will not be attempted and prevention of the disease 
cannot be assured. However, information will be provided in relation to the importance of 
knowledge to be gained and future intervention studies to prevent further cases of konzo. Subjects 
who agree to participate in the study will be asked to mark the consent document with an “X” by 
the side of the individual’s name, as witnessed by the signature of the research assistant obtaining 
consent. They will also be asked for permission to record their face and their children(s) face 
photographically for the purposes of verification of the enrollee in future years. Whether 
permission for a photograph is granted or not, a unique number will be assigned to the enrollee 
and the number written on the document and photograph. Subjects who decide not to participate 
will not be asked to mark the document or to be photographed. 
E. If consent will not be obtained, explain why. Describe why the research could 
not be practicably carried out if consent was required. If the research involves 
identifiable private information or identifiable biospecimens, describe why the 
research could not practicably be carried out without using such information or 
biospecimens in an identifiable format. 
 Not Applicable 
       
F. If your study involves use of a consent form, complete i, ii, and iii.  
 Not Applicable 

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i. Select the appropriate option(s) below for the documentation of consent.  
 Will use a written consent document signed by subjects 
 Will use a short form written consent document signed by subjects 
 Will not obtain a signed consent document for some subjects 
 Will not obtain a signed consent document for all subjects 
ii. Describe when and how the subject will receive a copy of the consent form. 
 A copy of the consent will be given to the caregivers after signatures are completed 
iii. If subjects will not be signing the consent document, please explain why. If 
some subjects will not sign the consent document, explain who will and will not 
sign the consent. 
 Not Applicable 
       
G. If the study involves cognitively impaired adults, explain the process to 
determine whether a subject is capable of consent, use of any legally 
authorized representative(s), and any assent process.  
 Not Applicable 
       
 CLICK IRB: Upload any assessment tools to the Supporting Documents SmartForm page. 
14. Coercion or Undue Influence.  
A. 
 
If some or all of the subjects are likely to be vulnerable to coercion or undue 
influence, such as children, prisoners, pregnant women, mentally disabled 
persons, individuals with impaired decision-making capacity, or economically 
or educationally disadvantaged persons, describe additional safeguards that 
have been included in the study.  
 Not Applicable 
       
B. If you or your study team are associated with the subjects (e.g. your students, 
employees, colleagues, patients), explain the nature of any association and 
measures taken to protect subjects’ rights, including safeguards against any 
coercion or undue influence (e.g. pressure a subject might feel to participate 
based on the association).  
 Not Applicable 
       
15. Privacy.  
 
How will subjects’ privacy be protected? Consider the number of individuals interacting with the 
subject or subject’s records, location of consent process and study, presence of individuals not 
associated with the study, sensitivity of the research.  
The potential for loss of confidentially is a serious threat that will take several training and 
procedural steps to minimize.  The requirement of treating health information as confidential will 
be strictly emphasized for all staff as part of training prior to study initiation.  All staff will be 
required to undergo certified training on human subjects’ protection including the imperative of 
strictly adhering to confidentiality enhancing measures.  All staff will be specifically trained to know 
that no one involved in this study is authorized to ever reveal/discuss participants’ health 
information with third parties and that evidence of such violation will be associated with strict 
penalties including the loss of employment. 
The first page of the risk-factor questionnaire, which contains identifying information, names and 
addresses, is removed after data entry and stored at INRB in a locked file dedicated to this 

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research study. The data files include only study numbers, which are linked through a security 
system, to a named file maintained for the purpose of informing individuals of information pertinent 
to their health. The name file is only accessible to the PI of the Kinshasa sub-contract (INRB), 
Professor Desire Tshala-Katumbay (R01 PI), and Professor Michael Boivin (R21 PI). The 
computer files are password-protected to ensure data security. All results will be reported in the 
aggregate. All data (including questionnaire, clinical, molecular) biomarkers are stored on a 
dedicated computer at INRB equipped with a back-up system. A tracking system will use unique 
ID numbers for all data files. These ID numbers will be used in the transfer of biomarker data and 
samples from the INRB to OHSU. Produced video/photo materials will be permanently kept by 
both the research team PI and the study participant. Flour cyanide and U-SCN surveillance date 
for the mother/child dyads, and neurodevelopmental and caregiver functionality mental health and 
HOME quality of caregiving data, all will be stored and managed in the MSU Biomedical Research 
Informatics Core (BRIC) secure server system (https://ctsi.msu.edu/bric) for access only by R21 
PI Boivin and Co-Investigators Familiar-Lopez (MISC and caregiver mental health) and Sikorskii 
(biostatistician and clinical trial methodologist). 
16. Withdrawal of Subjects.  
 Not Applicable 
If there are any anticipated circumstances where the researcher will withdraw 
subjects from the study regardless of the subject’s wishes, describe the 
circumstances and the procedures when subjects are withdrawn from the 
study. 
 
       
17. Monitoring Plan to Assess Data to Ensure Safety of Subjects. 
 
A. Is there a monitoring plan to periodically assess the data to ensure the safety 
of subjects or to ensure negative outcomes do not occur? 
 No 
 Yes 
Explain your answer. If you answered Yes, describe the monitoring plan. 
 
The University of Kinshasa Neurology Department and the Oregon Health and Sciences 
University are presently maintaining a formal research collaboration, under the direction of 
Professor Desire Tshala- Katumbay. Professor Tshala-Katumbay is PI of the R01 randomized 
RCT for the wetting method prevention of konzo, within which the proposed R21 will be 
embedded. They are presently sponsoring the formation of a standing data safety and monitoring 
board based at the University of Kinshasa Medical School as part of ongoing NIH and CDC 
sponsored clinical trials research program. Clinical faculty members from the bioethics program at 
OHSU are supporting this effort in the formation of a DSMB for the R01 study. Also, the MSU 
Office of Clinical Research (OCR) within the Institute for Clinical and Translational Sciences is 
also committed to supporting the Thrive Early psychiatry global research initiative in the formation 
and support of any DSMB relevant to our efforts. For the MISC caregiver training clinical trials with 
HIV-affected households in Uganda, that provided regulatory guidelines and lists of key 
membership from our program in Epidemiology, Biostatistics, and Bioethics and Humanities for 
the DSMB for those clinical trials. In the meantime, the R21, R01, and Sub-Contractor (INRB) PIs 
will be responsible for monitoring any adverse events notably breach of confidentiality related to 
home-based MISC training, emotional duress for caregiver evaluation of mental health and 
caregiving functionality, and profound neurodisability for study children that becomes evident from 
this domain of outcomes assessment. Monitoring will be done on a continuous basis. Any adverse 
events will be reported to the Institutional Review Boards (IRB) of participating institutions to 
ensure that appropriate action is taken. This is an appropriate strategy because the proposed 
intervention for the present R21 proposed study is behavioral in nature and very low risk. 
Likewise, the outcomes assessments specific to this R21 are on-invasive lab (urine thiocyanate 

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levels) or behaviorally based and established to be low-risk from prior use in our preliminary 
assessment work in the DRC with konzo-affected households. 
 CLICK IRB: Upload any data safety monitoring plans to the Supporting Documents SmartForm 
pages. 
B. If there is a data safety monitoring committee or board, describe the 
composition and frequency of meetings.  
 Not Applicable 
      
18. Results and Data Sharing. 
 
A. Could this research generate any results that could be clinically relevant, including individual 
research results, or general, or aggregate research findings? 
 
 No 
 Yes, clinically relevant individual research results 
 Yes, clinically relevant general or aggregate research findings 
1. If yes, explain what clinically relevant research results will be generated, whether they will be 
disclosed to subjects or others (e.g. subject’s primary care physician), and if so, under what 
conditions. Address individual research results and/or general or aggregate research findings, as 
appropriate. This also needs to be explained in the consent document. 
       
B. For other research results, select all that apply: 
 Not Applicable 
 Overall study results will be shared directly with subjects 
 Individual results or incidental findings of individual subjects will be shared with subjects or 
others 
 Data will be submitted to a repository or database as part of data sharing agreement (e.g. 
genomic data sharing) 
1. Explain your selection(s), including how the data or results will be shared and with who (e.g. 
subject’s primary care physician, data repository).  
       
19. Local Context and Multi-Site Study.  
A. Describe the locations of where the study team will obtain information or biospecimens through 
intervention or interaction with the subject or obtain the subjects’ private identifiable information.  
This study will take place in Kahemba, a district with the highest known incidence of konzo in the 
world. The district of Kahemba has been continuously affected by konzo since 1990. Residents of 
Kahemba rely heavily on cassava farming and possess very limited livestock (goat, pigs, chicken) 
for subsistence. During the last decade, the population of Kahemba has experienced a severe 
economic crisis due to the return of Congolese refugees from Angola with the end of armed 
conflicts in Angola. Due to food production shortfalls coupled with increased demand, residents of 
Kahemba have been forced to take short-cuts in the proper processing of cassava, a 
phenomenon that has led to an increase in food cyanogenic exposure. These short-cuts typically 
involve “short-soaking” the cassava (soaking the peeled tubers in water for less than the 3 days 
necessary for adequate fermentation), and failing to adequately dry the soaked tubers in sunlight 
(at least a day) before pounding the tubers into flour for storage.  Coincidently, an unprecedented 
rise in the number of konzo cases has been documented with prevalence up to 20% in certain 
villages. There is good field research clinical trial capacity so support our study in Kahemba 
because it is also presently the site of an NIEHS non-inferiority clinical trial. This R01 trial 
(2R01ES019841; PI: Tshala-Katumbay) is evaluating the comparative efficacy of peer- versus 

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professional-led wetting method training (WTM) of caregivers in an effective approach for 
detoxifying their cassava flour before consumption.  This approach is the standard of care for our 
present R21 study because it has been repeatedly demonstrated to reduce cyanogenic levels in 
poorly processed cassava flour to safe levels, even if the flour is initially very toxic due to short-
cuts that have been taken in the processing of the cassava 
B. If the study will engage employees or agents of non-MSU organizations (e.g. 
performance sites), explain how the employees or agents will be engaged (e.g. 
will they perform research procedures, will they obtain informed consent from 
subjects). 
 Not Applicable 
 
Research staff in DRC will be managed on-site by our local partners (PRONANUT and INRB). 
This is highly experience staff who has participated in previous clinical trials (a parent R01 to this 
application). All research staff will have completed Human Subjects Research training and will be 
in direct supervision by Drs. Kashala-Abotnes and Tshala, who will report directly to Dr. Michael 
Boivin (PI). 
C. If the study involves multiple performance sites, describe the methods for 
communicating with engaged sites related to the protection of human subjects 
(e.g. any potential unanticipated problems that may involve risks to subjects 
others). 
 Not Applicable 
 
Drs. Tshala and Kashala-Abotnes will oversee all study activities at each site and report directly to 
the PI (Dr. Michael Boivin) by email or call as needed. During the enrollment period, sites will 
communicate with the MSU PI and co-investigators on a weekly basis through a secure conferece 
call system to report on enrollment numbers and any issues encountered. 
D. If there are any cultural or local contexts or requirements that may impact the 
protection of human subjects or present additional risks to subjects that have 
not otherwise been described, please describe. If research is conducted 
outside the state of Michigan, this could include additional state or international 
requirements or laws. 
 Not Applicable 
 
This study will be reviewed by the local IRB in DRC (housed at PRONANUT) 
E. If translations to a language other than English will be provided to subjects, 
describe the translation process. 
 Not Applicable 
Consent and assent forms will be translated to the local language by local research staff and back 
translated for accuracy. Final versions will be reviewed by Dr. Itziar Familiar (co-I) 
 CLICK IRB: Upload translated documents to the appropriate SmartForm page(s). 
20. Resources and Financial Compensation and Costs. 
A. If someone will receive a payment for recruiting the subjects, explain the 
amount of payment, who pays it, who receives it, and why they are being paid. 
 Not Applicable 
      
B. If subjects will be compensated for participation in the study, provide details 
concerning payment, including the amount and schedule of payments 
including any terms and conditions. Payment should be proportionate to 
participation. 
 Not Applicable 
 
The Kinshasa-based PRONANUT and INRB study teams (sub-contractor) have carried out 
international research studies on cassava- based health problems and thus is known and trusted 
in DRC. Subjects will be recruited with the full knowledge, consent and support of tribal leaders 

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and with the knowledgeable assent of other trusted parties, including village leaders and resident 
missionaries or church leaders. These parties will be informed of the study purpose, namely to 
assess the interplay between the body’s structure and function and its exposure to natural 
substances in cassava. They will also be told that the initial and continued participation of the 
village and individual villagers is entirely voluntary. Participation includes answering a series of 
simple questions and providing sample of cassava flour, blood and urine at enrolment and in 
subsequent annual visits. Those who decide they wish to participate will be compensated 
equivalent of ~ $ 10 monthly in local currency for the duration of the caregiver training 
interventions, either WTM or WTM/MISC). 
Caregivers will be reimbursed for travel costs to the clinic visits up to $5 USD per visit 
C. If subjects will incur additional financial costs as a result of their participation in 
this study, explain the additional costs. 
 Not Applicable 
      
D. Describe any resources not otherwise described elsewhere in the submission 
(e.g. internal funding) for the protection of human subjects. 
 Not Applicable 
      
 CLICK IRB: Upload any funding materials not accessible in Kuali Coeus in the Supporting 
Documents SmartForm page. 
E. If subject’s biospecimens (even if identifiers are removed) may be used for 
commercial profit, describe whether the subject will or will not share in the 
commercial profit. This also needs to be explained in the consent document. 
 Not Applicable 
       
21. Information and/or Biospecimen(s) Management and Confidentiality. 
A. Select the appropriate option:  
 Identifying or coded information will not be stored with the information and/or biospecimen(s) 
 Identifying or coded information will be stored with the information and/or biospecimen(s) 
B. Please explain your selection. If you are storing identifying or coded information with the 
information and/or biospecimen(s), explain why identifiable or coded information and/or 
biospecimen(s) needs to be maintained and how long it will be necessary to maintain it.  
      
C. Describe the procedures and safeguards you will use to secure the information and/or 
biospecimen(s), including during transport of information and/or biospecimen(s). 
Procuring cassava flour samples and urine samples from villagers in Bandundu are routine 
activities for the INRB sub-contractor and the teams from the Congo Ministry of Health. They are 
experienced in collecting, processing, storing and shipping samples. Pre-printed labels with 
unique identification numbers are placed on each sample tube. Cassava flour and urine samples 
and their analysis are performed in the village setting, with results evident to both subject and 
investigator. The significance of the reagent-induced color change (density varying directly with 
SCN concentration) will be explained to the villager as part of the intervention. The SCN content 
and color of the urine sample will be entered into the questionnaire and the sample discarded. In 
the R01 study, additional urine, dry blood spots (DBS), and blood (serum/plasma) samples are 
being individually labeled for laboratory analysis of the different biomarkers (8.12-isop, pep1, 
pep2, and homocitrulline). Therefore, a good procedure is already in place in terms of securing the 
custody chain for handling specimens of this sort for our R21. Again, this information will be 
gathered before, at 6- and at 12-months following MISC training in coordination with the R01 

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study, and be made available for the proposed R21 study for co-enrolled caregivers and the very 
young study children in their households. In the present R21 study, urine samples are individually 
labeled with their unique ID numbers, flash-frozen or in a dry-ice refrigerated container as needed 
and transported to INRB Kinshasa. A transmittal slip (multiple copies) accompanies each sample, 
and a copy is retained in the study office chain-of-custody (COC) procedures ensure security of 
transportation from the origin (Bandundu villages) to destination (INRB, Kinshasa). The local study 
coordinator fills out a three-part check-in sheet using the sample tracking codes. The study 
number in combination with the sample number is identified as the key field, and all the 
information specific to the sample is referenced by the codes. The check-in sheet must be 
complete in order to track biological samples. After the check-in sheet is completed, the first copy 
is used to enter the information into the Sample Tracking Database and then filed with the 
laboratory liaison. The second copy is given to the Kinshasa project leader. The sample custodian 
compares each sample with its corresponding 
COC, then signs and dates the COC showing receipt at the warehouse. A three-part check-out 
sheet is used to enter data into the Sample Tracking Database and track sample location. 
Comparable COC procedures will be used for the secure mailing of samples from the DRC to the 
USA, for delivery to MSU (R21) and OHSU (R01). Unique sample ID numbers will be used by the 
OHSU study coordinators to register the samples upon arrival, with crosschecking of each sample 
on a listing provided by the Kinshasa dispatcher. 
Data are being entered into the secure database immediately after each batch of samples has 
been analyzed. 
22. Drug and/or Device Storage, Handling, and Administration. 
 Not Applicable 
 Describe the procedure and plan for storage, handling, and administration of the drug and/or 
device so that they will be used only on enrolled subjects and be used only by authorized study 
personnel. 
      
23. Future Research. 
 
 If the research involves the collection of identifiable private information or 
identifiable biospecimens, select the appropriate option: 
 Not Applicable 
 
 The subject’s information or biospecimens, even if identifiers are removed, could be used for 
future research studies or distributed to another investigator for future research studies 
 The subject’s information or biospecimens, even if identifiers are removed, will NOT be used or 
distributed for future research studies 
 Please be sure to carefully consider the appropriate option, as this needs to be explained in the 
informed consent and can limit what is done or used for future research. 
24. MSU Additional Information. 
 Not Applicable 
Identify if your study involves any of the following: (check all that apply) 
 Use of human stem cells 
 Research with biospecimens will (if known) or might include whole genome sequencing (i.e., 
sequencing of a human germline or somatic specimen with the intent to generate the genome 
or exome sequence of that specimen). If so, this needs to be explained in the consent 
document. 
 
 
 
Other Click IRB Document Uploads As Appropriate 
(Applicable to Expedited or Full Board Studies) 

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24 
 
• 
Upload list of external study team members (non-MSU individuals) to the Study Team 
Members SmartForm page, Question 2. 
• 
Upload other institution(s) approval letter(s), if submitted to other IRB(s) or ethics 
committees, to the Supporting Documents SmartForm page. 
• 
Upload FDA communications, package inserts, FDA form 1572, or other information 
related to drugs or devices to the appropriate Drug or Device SmartForm pages. 
• 
Upload the HRP-540 - Template - ICH-GCP - For Investigator to the MSU Additional Study 
Information SmartForm page. 
• 
Upload HRP-541 - Template - Involvement of Prisoners in a Research Project to the MSU 
Additional Study Information SmartForm page. 
• 
Upload the investigator brochure to the Supporting Documents SmartForm page 
• 
Upload the MRI Screening Form – Women to the Supporting Documents SmartForm page. 
• 
Upload the translation of instrument(s) provided to non-English speaking subjects to the 
Supporting Documents SmartForm page. 
• 
Upload the curriculum vitae(s) when research is more than minimum risk to the Supporting 
Documents SmartForm page. 
• 
Upload case report forms to the Supporting Documents SmartForm page. 
• 
Upload the Non-MSU Employee Conflict of Interest Disclosure Form to the Supporting 
Documents SmartForm page. 
• 
Upload any other pertinent documents related to the proposed research study to the 
Supporting Documents SmartForm page