(aka ‘Project Waldo’)
with extremely low-cost and maximal self-reliance
NOTE & Disclaimer: This whitepaper document is shared here as the ‘genesis thinking’ primarily in March-May 2020 for OpenCovidScreen and the effort to catalyze Frequent, Fast-turnaround, Cheap & Easy (#FFCE) testing to enable safe return to school & work, by helping catch occurrences before they become outbreaks. The document is no longer current, and is not an official document, or fully reflective of current thinking. But, it is historically significant and “interesting.” So, here it is!
DRAFT – As of July 2020
Original formatted version at: bit.ly/waldotest // Feedback to: email@example.com
(or “What if a high-quality COVID-19 viral test cost less than a latte?”)
The genesis for this project was a discussion with the administration of a ~300-student school, which was trying to answer a ‘simple question’ — with the current and expected state of the COVID-19 pandemic, “what do we need to safely resume school in September?”
Some of the constraints to answering the question include: the need for sufficiently frequent and accurate testing to enable effective “test, trace, and isolate” (“TTI”), the need for simple and safe sample collection for testing, managing risk of shortages and supply chain issues for test reagents & supplies (e.g,. swabs, PPE, commercial lab operators), and the need for a very low cost per test.
Unfortunately, there was nowhere near a simple answer to the ‘simple question’, and the question generalizes to many, many schools and universities, but also to small & medium-sized businesses (i.e., getting the economy functional again), and beyond to hot-spot sites like nursing homes, prisons, meat-packing plants, and much of the developing world without current access to complex/expensive testing infrastructure.
The goal of the proposed COVID-19 screening “Waldo Test” is to enable a low cost, effective, and realistically-implementable TTI strategy that takes inspiration from successful implementers like the country of New Zealand (which is currently among the lowest in the world in COVID-19 infections and deaths per capita):
“Elimination doesn’t mean zero cases, it means zero tolerance for cases. It means when a case emerges, and it will, we test, we contact trace, we isolate, and we do that every single time with the ambition that when we see COVID-19, we eliminate it. That is how we will keep our transmission rate under 1, and it is how we will keep succeeding.”
– Jacinda Ardern, Prime Minister of New Zealand, April 2020
There’s much more that needs to go into a full program, protocol, and policies for effective TTI, but this initiative started with an aspirational specification for a COVID-19 screening test that could be done frequently (at least weekly), and be simple and cheap enough that it could be done by nearly anyone with high-school level chemistry/biology understanding and with appropriate training in lab safety and “standard operating procedures” (“SOPs”) for this test. As a simplifying assumption, the focus of the test is screening (so could be “Research Use Only” / “RUO”), and would reflex (/refer) a positive result to an official clinical test with appropriate certification (e.g,. CLIA/CAP in the US) for clinical confirmation and any required follow-up medical action. Currently available COVID-19 testing options are sometimes bound by dogmatic “but that’s just the way it’s done” thinking; this is an attempt to start with first principles to innovate and achieve the simplest possible solution for these unprecedented times.
Topline: Surveillance/screening that is Frequent, Fast Turn-Around, Cheap, and Easy (“FFCE”)
To drive broader participation to innovate and create screening test assays that meet the target COVID-19 “Waldo Test” Specification, OpenCovidScreen.org will run a competition culminating in judging the week of August xx. It’s anticipated participants will range from graduate students/ PostDocs, to undergraduates, to high-school students. Outreach to proven labs and science mentors will ensure strong entries. Collaboration is strongly encouraged. Recognized deep subject matter experts from academia & industry will evaluate and award prizes in each category.
“WALDO TEST” VIRUS SCREENING ASSAY COMPETITIONS
In each category – First prize: $x00K; second prize: $x00K; honorable mention: $xxK each (depending on donor involvement).
Individuals or Teams create/define “open science” assays and demonstrate analytical validation performance (i.e., sensitivity, specificity, and limit of detection (“LoD”)) in their choice of category:
Categories 1 through 4 are based on currently known approaches for SARS-CoV-2 virus testing (see FAQs below for more details on each). The fifth, “Open”, category is intended to encourage innovation in new modalities and technologies for SARS-CoV-2/COVID-19 detection.
Judging will be based on:
“RETURN TO X” PROGRAM COMPETITION
Up to five finalists awarded $xxK each.
This competition evaluates programs proposed for implementation by individuals or Teams. Finalists will be recognized in back-to-school and back-to-work programs, and (depending on entries) may also be recognized in ‘hot spot’ categories (e.g., nursing home, prison, homeless community).
Why the name – ‘Project Waldo’? Is it an acronym for something?
The name takes inspiration from Ralph Waldo Emerson’s ‘Essays on Self-Reliance’. It also coincidentally references “Where’s Waldo”, where you’re quickly screening for a positive result (in that case an image of Waldo, in this case the SARS-CoV-2 virus). And of course every bio project has to have a tortured acronym, so – “Widely Accessible Low-cost Diagnostic via Open Source” for COVID-19 screening. If you don’t like it, please propose a better one (e.g., Project Jacinda?)
What is the mission & philosophy of Project Waldo?
Project Waldo’s mission is to enable “high-quality COVID-19 screening/ surveillance with extremely low-cost and maximal self-reliance”.
The solution needs to be ~simple, distributed, global (/possible anywhere in the world). Project Waldo aims to provide an “open source” high quality COVID-19 screening test protocol, playbook for implementing, and essential training materials so that COVID-19 screening can be implemented successfully nearly anywhere.
How do Waldo Tests fit in the landscape of other current test offerings?
What kind of test is the Waldo Test – viral (/molecular), or antibody, or something else?
Given the dynamics of COVID-19, the Waldo Test is a viral (/molecular) test detecting evidence of SARS-CoV-2 from the test subject, which is at peak in the range of -2 days to +7 days from initial symptoms. Antibody tests are also useful in TTI approaches, particularly for baselining who in the population has previously had COVID-19, but antibody signatures (IgG and/or IgM) are detectable in the range of +5 days to +20 days (and beyond) after initial symptoms. For the purposes of a TTI containment strategy to minimize COVID-19 in a population, frequent viral testing enabling early detection (with corresponding fast “trace & isolate”) is a more relevant mechanism. [TODO: links to COVID-19 viral load & antibody kinetics]
What are the leading options of how the test may be implemented?
As of late May 2020, the leading-contender platforms for the Waldo Test are LAMP, RT-PCR, CRISPR, or next-gen Sequencing:
RT-LAMP (“Reverse Transcription Loop-mediated isothermal Amplification“) – See inspiration from this pre-print on “Rapid Isothermal Detection of the COVID-19 Virus and a Framework for Scalable, Global Surveillance”. The pre-print is for swab-based collection and uses RNA extraction; remaining work would be to adapt for saliva self-collection, (ideally) remove the requirement for RNA extraction, and build basic input/output automation. Update Apr 29: another pre-print “SARS-CoV-2 On-the-Spot Virus Detection Directly from Patients” (tweet) confirms the potential for saliva + RT-LAMP + no separate RNA extraction step; needs some more work on optimizing sensitivity & specificity and scaling (e.g., tube strips or 96 well), but promising. Update May 19: More LAMP isothermal inspiration from Christopher Mason’s Weill Cornell team: “Shotgun Transcriptome and Isothermal Profiling of SARS-CoV-2 Infection Reveals Unique Host Responses, Viral Diversification, and Drug Interactions.” Update June 4: From Rabe & Cepko at Harvard: SARS-CoV-2 Detection Using an Isothermal Amplification Reaction and a Rapid, Inexpensive Protocol for Sample Inactivation and Purification
RT-PCR (“Reverse Transcription Polymerase Chain Reaction“) – PCR tests are the dominant form of clinically & commercially available testing for COVID-19 available today. They have the benefit of being relatively cheap (marginal cost of $10-15 per test), relatively fast (a few hours of time ‘on machine’ in the lab, typically resulting in next-day results at-best), and fairly accurate (high analytical sensitivity & specificity, somewhat lower real-world sensitivity due to viral load kinetics and collection technique & issues with nasopharyngeal swabs (“NPS”)). PCR machines are widely available and relatively inexpensive. There is currently high demand for PCR equipment and consumables, which are stretching supply chain capacity; it is expected the supply chain issues in North America & Europe will sort out over the next 12 months, but there is remaining risk for Fall 2020/Spring 2021 timeframe, particularly if there is a 2nd (or 3rd or more) wave of COVID-19 infections. Innovations in PCR like ChromaCode’s multiplexing/pooling approach can increase capacity and reduce consumables cost (by 4-10x) for COVID-19 testing. Most PCR-based COVID-19 testing protocols also require a RNA extraction step; it would be highly desirable to remove this requirement.
CRISPR (“Clustered Regularly Interspaced Short Palindromic Repeats“) – CRISPR-based SARS-CoV-2 tests are not yet commercially available, but multiple are in development. These have the potential of enabling low-cost (e.g., $10/test), fast (5-15 minute result), lab-based, point-of-care tests (benchtop device) or at-home (consumer-device) tests. While CRISPR consumer form-factor device tests have the potential to be a ‘sentinel test’ for applications like testing visitors to a location (e.g., school, hospital, restaurant, event, workplace, country-level customs/immigration), the fact that they’re not yet available in the market and that their unit cost is higher (perhaps 2-3 lattes!) means that they’ll be a stretch for repeated testing of a full population at a location (e.g., students & faculty full time at a school, all employees at a workplace, all residents & workers at a nursing home). Examples of current CRISPR-based R&D for COVID-19 testing with good performance that could be adapted for a simple, low-cost, lab-based test include this Mammoth/ UCSF collaboration: CRISPR–Cas12-based detection of SARS-CoV-2 or MIT/Broad’s ‘STOPCovid’ CRISPR assay.
Next Gen Sequencing – [TODO: May be challenging for this application since capital and consumable cost is higher, sequencing equipment is relatively more rare, and turnaround time is likely longer than 12 hours/“next morning”. That said, there are some very interesting approaches for infrequent massively-scaled testing using barcoding & pooling, like “LAMP-Seq: Population-Scale COVID-19 Diagnostics Using a Compressed Barcode Space,” that combine LAMP and sequencing. Other complementary approaches summarized here: “Fast and accurate diagnostics from highly multiplexed sequencing assays.” Commercial offerings are expected from companies like Guardant, Illumina, Helix, and Color Genomics.]
[TODO: Other approaches, like antigen testing with lateral flow, e.g., E25bio]
The final determination of which approach is the winner for the Waldo Test will be based on demonstrable test accuracy/ performance (as measured by sensitivity & specificity; false-negative & false-positive rates), biosafety, complexity and consistent repeatability, wide availability in the supply chain for the required consumables, and low cost (equipment, supplies/consumables, and unit cost).
Who else is using the OpenCovidScreen “FFCE” model for safe Return-to-Work/School?
As a reminder, “FFCE” is COVID-19 surveillance/screening that is Frequent, Fast Turn-Around, Cheap, and Easy. There are a growing number of organizations who are getting close:
|Frequent||Fast Turn- Around||Cheap||Easy|
|Return to X program||at least weekly, w/ sub-sampling||“next morning” results (or faster)||“less than the price of a latte” per result||self collection: saliva or AN swab|
|Major League Baseball (MLB)||✔️||✔️|