The Human Placenta Project

Circulating Factors - Premeeting Discussion Summary

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Key Achievements & Breakthroughs

  • Description and potential roles of placental extracellular vesicles (EVs)
  • Circulating RNAs, placental microRNAs
  • Advances in genomics, sequencing technologies & cfDNA field
  • Bioinformatics advances integrating information across different omics datasets
  • Recognition of placental sexual dimorphism
  • Discovery of placental cells shedding into the cervix
  • Recognition of protein misfolding in preeclampsia & congophilia as biomarker
  • Successes and failures of biomarkers in other fields (e.g. cancer, CVD)
  • Lessons learned from validation studies of placental serum biomarkers (e.g. sFlt-1 & PlGF)
  • Lessons learned from validation studies of placental microbiome

Knowledge Gaps

  • Incomplete understanding of normal variability (biological noise) across gestation
  • Poor clinical definition of pregnancy diseases and pathophysiologic heterogeneity
  • Gaps in pathophysiologic understanding of diseases where placenta plays a key role
  • Incomplete understanding of source and significance of EVs, cfRNA and potential biomarkers
  • Lack of measurements and understanding of first trimester
  • Poor understanding of how the placenta adapts to the environment
  • Incomplete understanding of impact of race, sex, diet, exercise, SES, maternal/paternal history – need multiple adjustments
  • Incomplete understanding of how placental health informs long term outcomes
  • Connecting factors with relevant outcomes or treatment options (qualification)

Opportunities to Fill Gaps in Knowledge

  • Develop large longitudinal cohorts to allow unbiased discovery – "deep phenotyping" paying attention to patient and disease heterogeneity with clear indication of gestational age
  • Collect the corresponding clinical data in a standardized, harmonized format
  • Provide road map for biomarker discovery, qualification and validation
  • Provide "fail-fast" reproducibility pipeline of "promising" biomarkers
  • Provide individuals with strong bioinformatics training
  • Provide individuals trained in multidisciplinary collaborations and team science

Technical Gaps

  • Disparity among methods for EV isolation and characterization
  • Technological gaps in analytical methods that measure low levels of analytes (e.g. proteins)
  • Technological gaps in analytical methods with rapid result turnaround
  • Technological gaps in analytical methods that are cost-effective and feasible for LMIC
  • Challenges of aligning longitudinal cohorts
  • Lack of standards for sample collection and processing (pre-analytical)
  • Lack of understanding how sample processing and age changes native state (pre-analytical)
  • Lack of longitudinal collections of biological samples with frequent sampling and corresponding clinical data

Opportunities to Fill Technical Gaps

  • Provide clarity to the EV and RNA fields (methods)
  • Need benchmarking studies and consensus for sample collection, processing, analytical methodologies
  • Use multimodal approaches
  • Need novel logistical models of repeated low-cost non-invasive sampling
  • Need well defined reference samples for gestational age
  • Can exploit use of different specimen types e.g. urine, saliva
  • Challenges to advancing circulating factors as clinical biomarkers
  • Difficult in absence of pathophysiological understanding
  • Fragmented knowledge: clinical, basic science, bioinformatics
  • Many factors are found increased or decreased – few qualify as biomarkers
  • Normal biological variability and variability in etiology of pathology
  • Rationale in absence of effective treatments
  • Need biorepositories of well characterized samples with abundant standardized, harmonized clinical data
  • Need consensus on clinical priorities & context of use for sought factors (needs assessment)
  • Need consensus on stakeholders
  • Need individuals with broad and in-depth knowledge able to work in teams
  • Few biomarkers are subject of patent applications

Future Opportunities

  • Blue skies vs. applied research approach – both have merit
  • Focus on important clinical problems where biomarkers inform different clinical choices
  • Increase basic science footprint linking placenta health to future maternal and child health
  • Successes without biological understanding have been possible
  • Learn from mistakes in other fields
  • Break down problem within FDA framework:
  • ─ qualification
  • ─ method of measurement
  • ─ context of use
  • Increase the pool of stakeholders (health of the placenta as window to future health)
  • Incentivize private sector (currently a limited stakeholder)
  • Train scientists with business mindset to build bridges across the "valley of death"

Which theme and set of objectives does your response address? THEME B: Circulating Factors

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