CHild malnutrition & Adult NCD: Generating Evidence on mechanistic links to inform future policy/practice (CHANGE project)

THE PROBLEM:
Child malnutrition is a major global public health problem and includes both undernutrition and overweight/obesity. Wasting (low weight-for-height) is a particularly severe form of undernutrition. Affecting some 49 million children globally, it contributes to 900,000 deaths per year in children aged <5 years (12% of total deaths). Whilst severe malnutrition treatment programmes do exist, problems limiting their success include the need to:
a) ENSURE THAT CHILDREN THRIVE AS WELL AS SURVIVE
Current programmes focus on averting the immediate risks of malnutrition-associated death. They don't account for increasing evidence that survivors often fail to thrive and are at greater risk of non-communicable disease (NCD) in later life e.g. heart disease, diabetes and obesity. Mechanisms causing this are poorly understood.
b) UNDERSTAND & MEASURE MORE MEANINGFUL OUTCOMES
Current programmes focus on return to normal weight as a marker of success. What really matters however is health. Predicting future ill health is especially difficult since risks laid down in childhood do not become apparent as adult NCD till many years later.
c) QUESTION ASSUMPTIONS ABOUT WEIGHT GAIN
Current programmes often see rapid return to normal weight as desirable and thus encourage fast catch-up growth. However, studies in high income countries show that too rapid a weight gain in small infants causes harm by increasing risk of future NCDs. Whether this also applies to low-income settings is unknown.

THE PLAN:
AIMS: To improve future treatment programmes by better understanding how child malnutrition affects the risk of long-term (adult) NCD.
OBJECTIVES: 1) To understand how the speed and pattern of post-malnutrition weight gain affects the risks of adult NCD
2) To develop simple blood/urine tests to predict which survivors of child malnutrition are most at risk of future NCD

THE TEAM:
We will bring together teams from 4 countries: Jamaica, Malawi, Ethiopia, UK and combine clinical and lab data from 4 groups (cohorts) of adolescents/adults who survived early life malnutrition. In Ethiopia and Malawi, we will recruit 2 more cohorts of at-risk infants so we can learn from their progress. Combining these datasets and bringing together varied scientific skills and disciplines will achieve together what no one team could achieve alone.

THE BENEFITS:
1) PROGRESS TOWARDS THE 2030 SUSTAINABLE DEVELOPMENT GOALS (SDGs)
If we succeed in our aim of informing better future treatment programmes we thus contribute to two major SDGs and their targets:
>>SDG 2 (END HUNGER)
>> SDG 3 (GOOD HEALTH & WELL-BEING)
These in turn impact numerous others e.g. education, economic development
2) ENHANCED MALNUTRITION-RELATED ADVOCACY
Effective advocacy is vital to generate the sufficient political will and sufficient resources to tackle malnutrition. The 'double-burden' of malnutrition (i.e. coexistence of undernutrition alongside overweight/obesity/NCDs) is increasingly common even in the world's poorest countries. By describing how one form affects the other, we hope that researchers, policy-makers and nutrition programmes managers will better be able to balance short vs long term risks and focus on 'double-duty' actions benefitting both. This could open up valuable new funding streams. It could also be a more effective and cost-effective solution to the global NCD epidemic.
3) IMPROVED SEVERE MALNUTRITION TREATMENT PROGRAMMES
Likely changes would be minor and thus easily/rapidly scalable, e.g. use of the same therapeutic foods but prescribed at lower dose so that weight recovery is neither too slow nor too fast.
4) NEW BLOOD/URINE TESTS TO MEASURE NCD RISK IN MALNOURISHED CHILDREN
Being able to measure a problem is key to tackling it. Simple new tests arising from our work would enable researchers/programmers to better understand if nut.>NCD programmes are succeeding.

WP1: DATA SYNTHESIS/STANDARDIZATION
Our project involves data from 7 distinct patient cohorts. We will first harmonise available datasets, highlighting common variables & agreeing on joint data strategies & definitions of exposure/outcomes

WP2: UNDERSTANDING HOW POST-MALNUTRITION-WEIGHT-GAIN (PMWG) INFLUENCES RISK OF NCD (towards objective 1)
Existing data from 3 prospective cohorts forms a natural experiment whereby:
-Jamaica-LION involved inpatient treatment for malnutrition and overall had the fastest rates of PMWG
-Ethiopia-ACAM was outpatient-only and had slowest PMWG
-Malawi-ChroSAM was mixed in/outpatient and had intermediate PMWG
Secondary analysis will explore inter-?ra-site PMWG and its association with NCD variables already captured in the datasets

WP-3: DESCRIBING BIOCHEMICAL CHARACTERISTICS OF MALNUTRITION SURVIVORS (obj. 2a)
Old blood samples from J-LION, M-ChroSAM, E-ACAM cohorts will be combined with new blood/urine samples collected from Malawi-2002-4 and Ethiopia-1980s famine cohorts. Metabolomic and lipidomic analysis will attempt to identify differences between: malnutrition survivors vs controls; survivors with/without NCD

WP-4: DESCRIBING BIOCHEMICAL PROFILES OF DIFFERENT PATTERNS OF PMWG (obj. 2b)
Blood/urine samples will be collected from two new cohorts: an observational birth cohort in Malawi; a cohort nested in an Ethiopian RCT. Metabolic/lipidomic profiles of different post-malnutrition growth patterns will be described

WP-5: IDENTIFYING BIOCHEMICAL SIGNATURES LINKING PMWG & NCD RISK (obj. 2c)
Data from WP3&4 will be compared. Biochemical markers common to early malnutrition/PMWG and later NCD can be used in future work as early markers of NCD risk

WP-6: GRIPP (Getting Research into Policy/Practice) & Stakeholder engagement/research co-creation (towards overall AIM)
Qualitative work will explore views of PMWG & malnutrition/NCD risk. A follow-on RCT will be co-created with key stakeholders to maximise impact

Main potential impacts arising from our work include:
1) PROGRESS TOWARDS THE 2030 SUSTAINABLE DEVELOPMENT GOALS (SDGs)
We focus on child undernutrition and later life NCD. If we succeed in our aim of informing better future treatment programmes we thus contribute to two major SDGs and their targets:
>>SDG 2 (END HUNGER) Target 2.2: End all forms of malnutrition, including achieving ... internationally agreed targets on stunting and wasting in children
>> SDG 3 (GOOD HEALTH & WELL-BEING) Target 3.4: Reduce by one third premature mortality from non-communicable diseases through prevention & treatment
These in turn impact numerous others since nutrition and health are closely related to: the ability to benefit from education (SDG4); gender equality (SDG5); employment (SDG8); inequalities (SDG10)

2) MALNUTRITION-RELATED ADVOCACY (incl. "Double Burden", "Double Duty" advocacy)
Effective advocacy is vital to generate the sufficient political will and sufficient resources to tackle malnutrition. Though "positive" results are often easier to work with, advocates can use even 'negative' studies to highlight needs and lobby for resources. Ours is thus a 'safe' investment. Even in a worst case scenario that we don't succeed in our project objectives (identifying PMWG as a mechanism towards future NCD; identifying NCD biomarkers) we can still make valuable contributions towards local, national and international advocacy efforts in the field. Whatever our final results, our work will:
>> Highlight that undernutrition and overweight/obesity/NCD are important and related problems needing urgent solutions through "double duty actions" which benefit both
>> Inspire others to search for other mechanisms/biomarkers (or elucidate further details of ones we do identify)
For this reason, advocates will be among our stakeholders in WP6. Our dissemination plans include:
>> Direct advocacy - via papers, reports, social media posts we write & events we organize
>>Indirect advocacy - via policy briefs and result we share to other advocates to use in their work.

Among our advocacy messages we will note that climate change is a serious global threat and there is a real danger that natural disasters will lead to resurgent food crises and famines: this makes the task of optimising treatments for undernutrition as important as ever.


3) IMPROVED SEVERE MALNUTRITION TREATMENT PROGRAMMES
We focus on PMWG as our key "nutrition>>NCD" mechanism since potential for it to be directly modifiable is high. This would be done via small, hence scalable, changes to the dose of therapeutic food prescribed in severe malnutrition treatment packages. We acknowledge that RCT-level evidence would be needed to verify our project findings experimentally before wide-scale change to current protocols. It is to speed this process that we directly include planning of such an RCT into our project timeline.

4) NEW METRICS (NCD BIOMARKER TESTS) TO MEASURE PROGRESS
Measuring a problem is key to tackling it. It is very rarely possible, even in research contexts to track malnourished children till adulthood to determine whether or not they develop NCD. If our search for early-life biomarkers of preclinical and clinical NCD risk succeeds, then such long term follow-up will not be needed. Benefits of an intervention on NCD can be assessed much earlier in life via presence/absence of those biomarkers. This will help others in the search for 'double duty' actions and interventions