My “Reverse Graduation” Speech

I had a chance to welcome the class of 2025 this week. The ceremony took place in the large and well ventilated arena with thousands of masked and vaccinated students looking on. A bit scary, but a milestone to be sure. Everyone had to have a negative PCR test to enter. They put me on the agenda right behind the student speaker who is a speech and debate champion….not nerve wracking at all! Anyways, here is what I said (slightly edited):

Wow, class of 2025! You made it! Some say showing up is half the battle. But this year, showing up is a complete, hard-fought victory. You’ve done a lot to get here, and we have been working hard to make sure that the university is the best and safest place for you to be right now. I’m going to tell you a little of the story about how people across this great university, some of them with us here today, came together to make welcoming you and your families possible.

But first let’s talk a bit about how stunning it is to be here all together in this place after the last 18 months. This is certainly an intense way to get back into speaking in front of students! The last time I gave a speech like this was at my 8th grade graduation in 1986. Our class of about 50 graduated that year and went on to enter a regional high school class of almost 1000. 35 years later, I have no idea what I said, and the notes are lost to history, but I remember being terrified.

There could have been a nugget or two of advice from a 13-year-old me that might have been helpful to you today – but not likely much. You have already lived a life that I could hardly have imagined in 1986. You have endured a pandemic, the sometimes-explosive reexamination of racism in this country, the pressures of climate change and more. Coming of age in this time and place has challenged your mental and physical health, strained your finances, and for many of you has meant the loss of family and friends.

I must tell you, while this has been a tiring two years, we know you enter college hopeful and full of high expectations for yourselves and for this place. We aim to meet those high expectations and make your time here rewarding and life changing.

The town I grew up in was about ten times smaller than the population of this university! I am sure that this is true for many of you as well. We all come to this place from other places, and we bring our memories, traditions, and hopes with us. You have moved from something smaller to something bigger, with more opportunities that you can imagine. Those opportunities are accessible online to be sure, but many of the serendipitous meetings and experiences that will change your life can only happen in person. When I was a freshman at Northwestern University, I was planning on being a journalism major. I had been the editor of my high school newspaper. I had not taken any science AP courses, since my high school counselor didn’t think that would be useful for someone who wanted to be a writer. But during freshman orientation week, I had some time to kill, and I was wandering around campus. I bumped into a tour at the engineering school and followed along. I found myself in a small dark room watching a scientist use a scanning electron microscope. After that tour I changed my mind about my major and re-registered for engineering classes. What was she looking at? What minute wonder of the universe caused me to change the direction of my entire life? She was watching cement dry. Hardly Earth shattering! But it was cool, and it was small, and it was beautiful to me. I wanted whatever my job was to involve studying the world at that size scale. A serendipitous meeting. A life changing moment. It could only have happened in person.

Those moments await you around every turn. The expansive and collaborative nature of this place is what makes it great. In my 18 years here I have run a research laboratory that has been home to students from engineering, the college of arts and sciences, the school of public health, and the school of medicine. In my lab, we work to bring new technologies for miniaturized medical diagnostics to underserved or unserved populations. My involvement in this work is how I came to be the Scientific Director of the Clinical Testing Laboratory.

Soon after we went remote, it became clear to many of us that with the available knowledge at the time that the university would not be able to open safely in fall 2020 without routine molecular testing for COVID-19.

In April 2020, the university president sent me an email.

Dear Cathie,

I hope you are safe and well. I suspect, like me you are about to go crazy staying at home. [Note this was only 5 weeks into lockdown!]

…I am very interested in pulling together the resources to do high throughput testing for COVID via PCR.  We don’t have a great deal of time to have this up and running by mid-August.  The project needs organization and leadership. Are you interested in being involved?

Please let me know…

I responded immediately in the affirmative. After all, my entire professional life had been focused on diagnostic testing. My lab works on making these tests small and accessible to communities without highly instrumented laboratories. Although I had spent my entire career up to April 2020 trying to make things that do not require sophisticated laboratory equipment, it was immediately clear that to keep the university open, such laboratory equipment would be required.

For the first couple of weeks, our team was small. Members of my laboratory were quickly joined by colleagues in Electrical and Computer Engineering. Our expertise in molecular testing combined with theirs in programming liquid handling robotics set the foundation of the team.

The earliest work, during a time when the dangers of contracting COVID-19 were still largely unknown, was done by graduate students, post docs, and a couple of newly minted grads. Together we built a plan, tracked down costs, interviewed suppliers and gathered information from teams that were starting similar projects at other colleges and universities around the country.

Once the president gave us the go ahead to proceed, our team grew to include lawyers from the general counsel’s office to help us navigate the regulatory landscape. Soon after that we needed the procurement group to help us secure the necessary equipment and supplies in a very uncertain marketplace with rapidly changing supply chains. Next, we had to leverage the facilities and building management apparatus of the university to set up places to collect up to 6500 swabs a day. As we worked, people on other teams reinforced student and employee health services, upgraded ventilation systems, redesigned move-in procedures, made and posted thousands of new signs, communicated our plans to the community, worked with the city and state departments of public health, and built new IT systems to make all of it work together.

It wasn’t a perfect roll out, but it was very very good. This project was the most challenging and, in my opinion, the most successful and rewarding project of my career.

Twelve weeks later, In July 2020, we delivered our first test results to students on the medical campus. By the end of August, we were routinely testing everyone on campus at least once a week.

By now you have all interfaced with the system that was put into place over those 12 weeks. I took my 14-year-old daughter with me when I dropped off my last test, and when we walked out she said, “That was it? They just scanned the tube?” I was a bit disappointed. Didn’t she want to know about those days last July when we frantically were calling the graphic designer at the company supplying the tubes because they did, in fact, not just scan? About any of the other road blocks and challenges that were coming at us like a firehose those first few months? Of course not.

All of the difficulties and minutiae that we dealt with, and the team continues to deal with, were invisible from the vantage point of the end user. As any good engineer or designer knows, the end user just needs the system to work. It needs to work so you can go to class, play sports, put on dance recitals, attend studio classes, or work on problem sets late into the night knowing that you are doing these things in the safest possible environment.

Nearly every time we needed to add people to the project with a particular skillset, we had those people already here, and they were eager and ready to serve. I encourage you to look closely as you spend time here at all the things that just work. The chairs set up in this room, the sound system amplifying my voice, the entire schedule of today’s events were all planned weeks and even months in advance. We have been waiting to welcome you and eager for you to contribute to this place in your own unique way.

These four years will pass by quickly, but they will be some of the most influential years of your life. The only certainty is that you will change. Many of you will change your major, like I did! Some of you will change it more than once! Some of you will change your pronouns. You will meet lifelong friends. Some of you will meet life partners. You are entering into an exciting new world of ideas.

I have certainly changed during my 18 years here. When I first arrived here I used walk by students during move in and see parents hugging their children goodbye. I saw all these new beginnings –  these launches of young people into a new phase of life. Now that I am a parent, as my girls approach college age themselves, it’s harder for me to watch families say goodbye. In fact, it now brings tears to my eyes. Interacting with the world in this way allows us all to appreciate our shared humanity. I’m sure we all appreciate being together again now more than ever.

The class of 2025 is remarkable already. As you enter this next phase of your life and education, I wish you the very best. Welcome. We are so very glad that you are here.

From the Dalkon Shield to Britney’s IUD

The answer is that the reproductive health of people who can get pregnant is simply not a high enough priority in our society. We settle for good enough when we could have great. 

Last week Britney Spears described how under her conservatorship, she was required to be fitted with an intrauterine device and is prohibited from removing it without her father’s permission or the permission of the court. Presumably the goal was to stop Ms. Spears from becoming pregnant with additional children without the express authorization of her custodian. 

Britney Spears from her Instagram Page.

There are many discussions to have about Ms. Spears’ rights, disability rights, and forced reproductive control. The topic is an intersectional minefield. An amazing discussion with a journalist who is an expert in the field and who has a disability was broadcast on What Next this week. My own thoughts on the subject would require me to use profanity on a blog that I know is read by my program manager at the NIH, and when I resort to profanity, that usually means I am out of comfortable intellectual waters. What I can discuss with a fair amount of authority is the IUD itself, its history in modern times, and how it has succeeded and failed as a medical device for people who want to avoid pregnancy. 

If you are my age (49) or older, you first learned about the IUD from horror stories told about the Dalkon Shield. The Dalkon Shield was an IUD invented in the early 1970’s by a gynecologist. Hugh J. Davis, was known as an intellectually arrogant person who didnt take criticism well.  So, it wasn’t a very inclusive design team – just one man. He later recruited Irwin Lerner, an electrical engineer, to help him finalize and market the device.  The device was rushed to market with insufficient clinical data, and the inventors published their pre-market data without acknowledging their financial interests in the device. They sold the device design to the A.H. Robins company, and Davis continued to act as a consultant and proponent of the device for many years. 

At the time, the birth control was popular, but the high levels of hormones in those pills were concerning to many.  The side effects of the pill were and still are troublesome and sometimes very serious. In the 1970’s, the available pills nearly 100 times more progestin and 3 to five times as much estrogen as what typical combination pills contain today.  Second, and probably more important, is the fact that the A.H. Robbins company did something new that we now take for granted: they marketed the ever loving heck out of that device. 

Dalkon Shield Marketing Material

Before 1976, you could invent and patent a new medical device that was meant to be inserted inside a uterus and worn for years at a time with absolutely no federal oversight. As a result, there were no regulations that limited or specified the set of materials to be used to construct the device. So, when the company decided to use a new material for the string, they were able to make that change without consulting any oversight body or performing additional testing to make sure that it was safe. 

It turns out that the filament they used for the string was made up of several smaller filaments, like a cable consisting of several smaller wires wrapped together. The little spaces in between the multi-filament string were small enough to give bacteria from the vagina a pathway into the uterus. These bacteria caused infections in people wearing the device that were later recognized as pelvic inflammatory disease. All told, the Dalkon Shield resulted in the injury of hundreds of thousands of women and the documented deaths of at least 18. 

The Dalkon Shield disaster is why medical devices are now regulated by the FDA, due to a federal law passed in 1976. Prior to 1976, only drugs were regulated. 

As a result of the Dalkon Shield injuries, deaths, and related lawsuits and finally recall, IUDs fell out of fashion in the US. Even though many other non-Dalkon devices existed, the market for IUDs was non-existent. The FDA approved the first new generation IUD in 1984, and that device was available in the US in 1988. Then several years passed before the current crop of modern IUDs began to come on the market from 2001-2016. These are considered Class III medical devices and require pre-market approval before they can be sold in the US. 

If a device failure occurs, doctors and patients are encouraged to report the failure to the FDA. Only distributors and manufacturers are required to report. The FDA compiles a database of these failures and though the reporting system is largely voluntary, the FDA does investigate to see if they are part of a pattern. Even the devices containing copper are considered to contain a drug, so must undergo stricter regulations required of drug/device combination products. Most agree that this has led to a very safe but short list of new generation IUDs available in the US. The downside of this enhanced regulation is that many devices approved in other countries that may be more appropriate for some people are not available here. The cost of obtaining FDA approval is too high to make selling in the US market attractive to foreign manufacturers. 

The stain of the Dalkon Shield has faded a bit. Younger people are more likely to seek and IUD as a long-term reversible form of birth control.  However, the legacy of birth control designed, developed, and marketed by people who cannot become pregnant is still a part of medical care today.  All the highly effective birth control methods have undesirable side effects. (Well, maybe not vasectomies, but that requires a monogamous relationship with someone with a good amount of self-knowledge and foresight for maximum efficacy – a rare situation). 

Everyone else must figure out what side effects and inconveniences we are willing to deal with to manage when we do and do not want to bear children, if at all. Why is the situation so dire? Why do we take the pill and risk life threatening blood clots at rates that are higher than those that temporarily stopped the use of some vaccines during a global pandemic? The answer is that the reproductive health of people who can get pregnant is simply not a high enough priority in our society. We settle for good enough when we could have great. 

One way to make better contraceptive choices a priority is to have people who can become pregnant directly involved with the design and development of contraceptive devices. Involved from the earliest stages. We need the viewpoints of these people as patients and as clinicians, designers, and engineers.  And we all need to think just a little more about each other’s healthcare. 

Simply, when the people who are the main users of a technology are not consulted in the design phase of that technology, the results for the end users are subpar and sometimes outright harmful. 

Diverse teams can save lives.   

As for Ms. Spears, it seems clear that her autonomy has been robbed without due process. Since you cannot remove an IUD on your own, she is effectively at the mercy of the state with respect to her ability to bear more children. Medical science may have given her a safer device than was available in the 70’s, but disability law has kept her rights in the 1920’s.

Building a COVID-19 Lab (3/n)

The “I swear, I am not trying to kill you edition.”

So that shopping post I promised last time? Yeah, life intervened. I had to get back to teaching the class that originally led to this blog fall semester and help put out the fires that kept popping up with the testing project all semester! Anyways, let’s get back to it. 

I want to take a look back at one of the more controversial parts of this project: communication. Communicating with a large, interdisciplinary team is always difficult. Much trickier is communicating with a large, interdisciplinary community of stakeholders.

We have an incredibly diverse university community. We have students who just graduated from high school who were showing up on our campus in their first foray into independent living, and we have faculty who have served the institution for decades. There are teachers who were facing the prospect of standing in front of large lecture classes, and facilities workers dealing with all matter of new protocols and work changes to most safely deal with the pandemic. 

My role was straightforward, to design and build a COVID testing facility on our campus. That work was done, and was running smoothly as the first students moved onto campus in early August. Our rates of positivity have been low (more on that in a future post), and the university launched a student led campaign to get students on board with the new protocols. Contact tracing was in effect, and the cases we identified in incoming students had been isolated. 

Sharing information with the community was part of my objective all along. I spoke to a number of local and national media outlets and continued to field questions to my email box every day.

I gave presentations to students, parents, faculty, and staff over zoom. A side effect of all of this one on one science communication is that I became, for a short time, the public face of an effort that was not welcomed by everyone on campus. Many believed that attempting to go back to residential learning was misguided, that it was too dangerous. Still others pointed out how going back to campus would impact our surrounding neighbors. Inequality of risk was a major concern. 

I shared many of these concerns. The pandemic had become far worse in the United States than I thought it would be. Leadership at the federal level was virtually nonexistent. At best, the federal government abdicated its responsibility, at worst, it spread false information that made people more anxious and upset and resulted in more illness and death than we would have seen had we had a coordinated effort from the top down from the start. I do hope better days are ahead of us in that respect. 

Given the year of no federal leadership, I decided that if I could help increase the testing in my state, I was going to lend my expertise to that effort. But, after I thought we were off to a good start, a lot of people started getting really snarky on Twitter.

Some of the comments were thoughtful. Some expressed real fears. I tried at first to answer them to the best of my ability. Answering questions about science is my job after all. But then a subset of folks came after me in ways that felt personal. And I started to get defensive. I swear, this widespread testing effort is not an evil plan to kill you or your students! After a couple of weeks of engagement, my husband quietly suggested that perhaps Twitter was not a good use of my time or that great for my mental health. And I took a step back. However, I think it is worth looking back at the main arguments from that time, because they are still important today. 

There were two conflicting arguments being made by my colleagues online. The first held that no matter what we do in terms of testng, tracing, and mask wearing enforcements, that undergraduates will never comply and we will all get sick in the end. The second argument warned against the university “blaming undergraduates” for failures resulting from the administration’s choice to bring students back to campus. We focused on the undergraduates because they were the largest group of people coming to campus from other places. Almost all of these other places had higher COVID-19 positivity rates than we had, so it was justified to keep our eyes closely on this group. 

Interestingly, in the end, neither of these things came to be. Nearly everyone, undergraduate to faculty, complied with protocols, and spread of the virus in the fall semester was much lower than in the surrounding communities. Ongoing analysis by my colleagues is forthcoming that will put numbers to this assertion. I also think that the overall communication coming from the university administration has greatly improved over the past 6 months as we have hit our stride. We start spring semester with similar fears and higher community numbers almost everywhere in the USA. We will continue to look at the on campus numbers daily, enforce testing compliance, and strive to keep our community safe.

For me, I have learned to use the block feature on Twitter. However, I have also opened new avenues of conversation via email and direct message with several colleagues who definitely disagree with our approach, but who also value ideas and reasoned arguments. These have been very rewarding interactions. I am still learning from this project, and will continue to be open to your comments and suggestions. I continue to remind myself that everyone is scared, and most are acting in good faith.

You are going to stick *what* up my nose? [Update with TikTok links!]

These are not your grandmother’s nasal swabs.

To continue our recent discussions on disease testing, today we’re talking about swabbing and swabs. 

Perhaps you’ve been lucky enough to experience a swab test firsthand. As testing becomes more widespread, we are all likely to have a nasopharyngeal swab taken for a  COVID-19 test. When I was a child, maybe around seven, I remember going to the doctor’s office to be tested for influenza, another virus that replicates in the nasopharynx. When the nurse first pulled the slim, wire swab out of the packaging, I thought no way. No way that daunting, 5-cm long wire will fit up my nose. Sadly, I was mistaken. I won’t lie – it wasn’t the most pleasant experience. The tickling sensation lingered in my throat long after the swab had been removed. I still felt it even after my results had come back – negative, luckily for me. Just a common cold! 

This kind of swab is referred to as a nasopharyngeal swab, which I learned many years later. Nasopharyngeal swabs are used to collect samples from the back wall of the nasopharynx (hence the name), which is where the nasal passages meet the throat. Other common swab tests include nasal swabs and oropharyngeal (throat) swabs.

Nasal swabbing vs. nasopharyngeal swabbing from link.

Swabs are made out of a number of different materials. Since the nasopharynx is much farther back in the nasal passage, the swab needed to get there must be longer and somewhat bendable. The swabs used for sampling the nostrils and throat are generally stiffer and shaped like long Q-tips. The materials that comprise the tips of these swabs are different, too. If you are trying to get material out of the oral or nasal cavities for testing, you need a surface at the tip that is good at grabbing that material. It is also important to be able to wash the material off and into the testing solution when needed. Thus, regular cotton is often not suitable. 

In terms of COVID-19 testing, the swabs you’re most likely to encounter are nasopharyngeal and nasal swabs. Nasal swabs are less invasive. The swab only needs to be inserted 1 cm into the nostril and rubbed along the septum for a few seconds. Nasopharyngeal swabs, on the other hand, require a longer swab, which is inserted about 4-6 cm back into the nostrils (about half-way between the entrance to the nares and the base of the ear). The swab is then rotated inside the nasal passages and left in place for a few seconds to absorb the sample. 

Check out Dr. Klapperich demonstrating anterior nares swabbing (AN) here and here on TikTok!

Swabs made to sample the nasopharynx usually have a tip made of plastic foam, or another material with lots of surface area. These are called “flocked” swabs. Only a few factories in the world make these swabs, which is why you regularly hear about swab shortages for testing. Sadly, using a version of a regular Q-tip would not be a suitable replacement. There are a number of innovative groups around the world looking for ways around this shortage. Some of them include 3D printing swabs made from medical grade plastics. All swabs that are used to apply topical medications or collect fluid samples are considered Class I medical devices by the FDA

In studies comparing the sensitivity of nasal vs nasopharyngeal swabs for influenza, nasopharyngeal swabs were found to be slightly more sensitive (94% vs. 89% sensitivity). This means that for the flu, a nasal swab sample will lead to a false-negative test result more often than a nasopharyngeal swab. But despite their inferior sensitivity, nasal swabs are simpler and useful for “self-swabbing”- taking your own sample to send or have delivered to a testing facility. According to the most recent update to the CDC’s COVID-19 specimen collection guidelines, nasal swabs taken by a healthcare worker or via self-swabbing are acceptable if taking a nasopharyngeal swab is not possible. But these guidelines are sure to change as more information comes out about how swab type affects false-negative rates for COVID-19. Early indications are that nostril swabs are not as good as nasopharyngeal swabs for this new virus. 

Building a COVID-19 Test Lab (2/n)

Last time we talked about how I got into this mess! Now let’s define the mess.

Last time we talked about how I got into this mess! Now let’s define the mess.

Ever had a great idea only to find out that someone else did your thing years ago? The high of thinking up something new is dashed by the realization that it wasn’t that new at all. Google has greatly increased the speed of this mental rollercoaster ride. I used to feel this disappointment acutely – but over time, I reframed it. Now when I see someone else doing my thing I think, “Damn, I’m not actually insane, that was a good idea!” 

Step one of this undertaking was to make sure that I was not insane. My first calls were to my colleagues at Boston Medical Center (BMC) who had started up an expansion lab to test more people at their site. The generosity of these folks cannot be overstated. Back in April they were still in the throes of the Boston surge, yet they gave me all the information, explanation, and time that I needed. They laid out the challenges ahead and linked me to the answers to my questions.

I then followed up with some very close reading of a preprint put out by the Berkeley team that outlined all of the hurdles they overcame to make their lab a reality. As I read through that paper, I was soothed. It was a blueprint with clear metrics for success – things I could get done. Then, I got to the last page of the preprint. It had an acknowledgements list of people who had helped the lab team get up and running. There were about 50 people on that list, and around 15 organizations. The magnitude of this endeavor became clear.

When a job is this big, you should first ask “can I just buy this?” In other words, can I pay money to leverage the invested time and expertise that others have already put in and get all of or most of what I need? It’s the difference between buying a fixer upper that requires a huge remodeling project, and just buying something move-in ready that you like well enough. The former may allow you to get every detail the way you want it, but the latter would be a whole lot easier in terms of time and aggravation.

Tests are expensive!

The major limitation to just buying from a testing service was cost. The big-box stores of laboratory testing were already struggling in April to promise COVID-19 test turnaround times of less than 3 days. On a campus like ours, with students, faculty, and staff coming and going on schedules, models showed that we were going to need 24 hour turnaround time, or it wasn’t going to make sense to test at all. So, the big testing companies were out. Other options available in the Northeast had price points significantly higher than what we knew the cost of materials to be, so we started to research in-house testing.

Turns out professors are a bit out of the loop when it comes to real-life project budgets – or at least I was! My idea of what physical things like reagents and instruments cost is usually an overestimate, since I’m usually doing one off experiments and almost never can take advantage of scale. My idea of personnel costs skewed in the other direction. Academic labs are home to extremely motivated and sharp young people who are working overtime to get their degrees at a rate significantly below what they will be earning the second they step out of our doors. For this project we needed to hire professionals with experience doing specialized testing. Same with space and overhead costs. It is often a conceit of those of us who bring in research dollars that we are “making money for the university.” Actually, most research active departments cost the larger organization money, while places like the law school bring in cash because they sell a high priced product that doesn’t take up a lot of specialized space! 

To condense a lot of spreadsheets into one sentence, I am happy to say that we were able to predict a cost per test in a new facility well below what we could get from any of our other options. 

Next time we will talk about procurement – or as I like to call it, shopping!

Building a COVID-19 Test Lab (1/n)

When the president of the university asked me to put together a plan for what an on campus testing site would look like for our large campus community, I said yes.

Initially, this was going to be a short little post about my experiences the past couple of months. Turns out this experience has been the most complicated and rewarding time in my career, and it will require installments! Also, in this manner I can make sure that all the info I am providing is fact-checked and that I don’t get out ahead of guidance we are giving to our campus community. 

I hope you decide to follow along. 

Back in late April, a couple of emails popped into my inbox about what I thought about the possibility of building an on-site COVID-19 testing lab at my university. I had watched colleagues do this at our medical school to expand their ability to test patients and healthcare workers during the early surge in Boston. Colleagues at UC Berkeley, my alma mater, were also doing the same for their campus. From afar I had admired their resourcefulness and ability to pull together these complicated undertakings in a few weeks, and even faster at Boston Medical Center!

Stock image of a large scale laboratory.

Yeah, I thought, we can do this, but we need either a lot of people to pipette, or robots. Graduate students, much to the chagrin of many in the academy, are not an infinite resource! Besides, like everyone else, they wanted to get back to their own disrupted lives and research.

I’ve always been into outbreaks. For me, they are like the true crime of science. I’ve read all the books. The villain is the microorganism. Sometimes the causative agent is a mystery or comes from a mysterious source. Sometimes we know exactly who the serial killer is, and we have to try and stop it. SARS-CoV-2 is a virus we are getting to know quite well. 

One of my favorite colleagues is an honest-to-goodness card-carrying Ebola researcher. On my last sabbatical, I expressed my fascination with BSL-4 work, and how cool I thought it would be to just quit my job and train up with him to do this work. Leave everything behind and chase these mysterious villains. His immediate response was, “You are exactly the kind of person who should NOT be doing this work!” Hopes dashed, I went back to the relative safety of working on point of care (POC) tests for sexually transmitted infections.

Then COVID-19 emerged. The world seemed to start noticing POC diagnostics, or tests that can be done quickly and close to a patient. Journalists were calling to ask my opinion on how fast something like that could get to the mass market for COVID-19. The federal government started throwing money (billions of dollars, with a B) at my area of research. The little obscure molecular test system I work on was suddenly on the tips of the tongues of every Super Fancy Research University scientist. 

What I worked 20 years to make myself an expert in was finally interesting to someone other than my mother! But designing and developing new tests takes time, and we do not have a lot of time with this virus. Perhaps for the next one, and there will be a next one, quick POC tests will be widely available and cost effective. For now, we have to go with the systems we have, and the fastest way to get a lot of people tested efficiently is to scale up existing molecular tests and make sample collection as easy as possible. 

So, when the president of the university asked me to put together a plan for what an on campus testing site would look like for our large campus community (35 – 50,000 people, depending on how you count), I said yes. 

Next time I’ll talk about steps one and two in every big engineering project: defining the problem space and consulting the experts. 

What we talk about when we talk about diagnostics.

After spending the last few weeks talking with students, journalists, neighbors and family members, I’ve decided that there might be some value in discussing some of the terminology that we use when talking about diagnostic testing.

Science communication and media relations folks always discourage “jargon” when describing scientific concepts to laypeople. However, technical terminology can be a key part of scientific discussions, especially when it’s important to be precise. Now, in the setting of a global pandemic, precision is particularly important, and I believe people can handle more complexity than the scientific community often gives them credit for. Increasing scientific literacy can empower people to better understand and digest current events. So, here are some of those definitions.

First off, is reagent. In general, a reagent is any substance that is a starting material for a chemical reaction. Do you remember finding the “limiting reagent” in high school chemistry class? That’s the chemical that runs out first; thus, limiting the amount of product that can be made by the reaction. Many outlets have reported that one of the reagents failed in the initial test that the CDC distributed for COVID-19. It is still unclear which reagent did not perform as expected, but the reagent was one of the parts of the test reaction that the CDC shipped out to labs around the country. This problem has now been fixed, and all of the CDC test components are working well. 

Negative and positive screening test cassette strips.

The next term is assay. Assay is just the word we use for “test.” Anytime you hear someone say they are running an assay or assaying for something, they are simply running a test. 

Controls and control material also come up often when discussing test design. Controls are needed to make sure that the test you are running is valid. Basically, controls are parallel experiments that you run alongside your testing to make sure that you didn’t make a mistake while running the test. We science folks are always skeptical and are always checking to make sure we didn’t make a mistake! A positive control, in the context of COVID-19 testing, is when we put some material in the reaction that we know will make the test come up positive. If that reaction does not come up positive, we know that we made a mistake someplace, or that some of our other reagents are not working properly. A negative control is when we set up a test that does not contain a sample or additional material, that we expect to come up negative. If a negative control comes up positive, then we know that we have some kind of contamination, or that something we did not expect is happening in our reaction. If this happens, we need to start over, and figure out what went wrong. In both cases, controls that do not work as expected render any test result invalid. These results are not reliable and should not be reported. 

Now, we need to cover sensitivity and specificity. These guys are a bit more complex. Sensitivity measures how little of the virus you can detect using a particular test in a particular sample. A super-sensitive test can detect very small amounts of the virus. Sensitivity goes hand in hand with the concept of a false negative. A test that is not sensitive enough might come out negative for someone who is infected with the virus, but does not have a viral load high enough to make the test read positive. It is also possible that a false negative can arise from a swab being taken improperly. 

Specificity is a measure of how well the test detects the COVID-19 virus, and not other things that might confuse the test. A very specific test is good at detecting COVID-19 and will not detect other closely related viruses. Specificity goes hand in hand with false positive rates. If a test is not very specific, it might show a positive result when someone is not infected with COVID-19, but with something else like a flu virus. 

Both false positives and false negatives make it difficult for healthcare providers to interpret test results in the context of care. Low rates of false positives and false negatives make a test more trustworthy. 

Now you know the basics of test design and metrics! We hope that this makes reading some of the science reporting a little more clear. 

Let’s Discuss Testing for COVID-19

The COVID-19 pandemic has sparked a great testing debate in this country, and you’ve likely heard a lot of terms thrown around: RNA tests, antibody tests, point of care tests, laboratory tests, etc. But what are the differences between them? When is each one useful? Not every test gives your healthcare provider the same information, and not every test is useful at every stage of an infection. 

In this post we will break down three things: the types of tests out there,  what information each test can give us, and when that information is useful. There are a lot of good explainers on this if you are interested in diving into the details, and some great resources are listed at the end of this article for more info! 

Let’s start by discussing the types of tests available. First, there are the nucleic acid tests that detect DNA and RNA. The SARS-CoV-2 virus that causes the COVID-19 disease is an RNA virus, which means that its genome is made up of RNA instead of DNA (like ours!). The RNA sequence is specific to that virus, and detecting its presence tells us if someone has been infected with the virus. This test will read as positive when the viral RNA is present, which can occur as soon as the virus is replicating in your body and until your immune system has completely cleared the virus. The amount of virus in your body is roughly proportional to the amount of viral RNA, since each viral particle contains a single RNA genome. Therefore, the amount of viral RNA in your body will change over the time that you are sick, and will go away when you are well and the virus is gone.

So, a test for the RNA, or a “nucleic acid test”, will be able to tell you when you are infected with the virus. The test will be accurate at any stage of infection as long as you have enough virus in your body. Whether you have been infected but aren’t showing symptoms, you’re feeling sick, or you’re starting to feel better, the nucleic acid test can still be positive if there is enough virus in your system. Viral load, or the amounts of virus in your body, tends to follow a pattern that starts low, peaks or levels off, and finally falls off as you get better. The amount of virus can vary from person to person at each stage of an infection. Factors like how old you are or if you are immunocompromised can alter how much virus is in your body during an infection. The variables that affect viral load for this COVID-19 disease are not yet well known. Learning more about these factors will help us get better at knowing when to test, who to test, and how to make better tests. 

The caveat about nucleic acid tests is that in most cases, they require a sophisticated laboratory set-up to perform.  This is one reason why it was difficult to ramp up COVID-19 testing in the United States. Not every lab is designed for this kind of work, which limits how many tests can be performed in a day. However, RNA tests can also be done on smaller test platforms in less sophisticated labs. These are called point-of-care tests, or POC tests. Recently, Abbott released a small scale POC RNA test for flu and other infections which interfaces with a testing system they already have in the field. The test can produce results in about 15 minutes, but only one test can be run at a time, while more sophisticated labs can run hundreds of tests or more at a time. There are about 18,000 of these instruments already in doctors offices and small labs around the country, and Abbott claims they can ship 50,000 test cartridges a day for these systems. 

Unfortunately, for a number of reasons, the United States has not invested the necessary capital and resources in POC nucleic acid testing and research. The technologies to make RNA testing portable and accessible do exist, but the cost/benefit ratio has not been favorable in the US — until now.  During a pandemic, when lots of people need tests, the economics do work. The conundrum, however, is that in normal circumstances, when a small doctor’s office is running only a few tests a day for different infections, it often does not make sense for them to have this testing on site. So, they use large lab testing companies instead. Samples from the practice are picked up like the mail by couriers and driven to central facilities for testing. The results are returned to your provider electronically. 

The COVID-19 pandemic has cast POC testing into the spotlight, making it evident just how essential it can be for disease containment. POC tests are often touted as a solution to healthcare inaccessibility in low resource settings, but the reality is that POC tests are vital to all settings. As more novel infectious agents emerge, we hope that even high resource countries will prioritize POC development.

When you first think of POC testing, what comes to mind? Many people think of urine-based pregnancy tests, which are widely available at drugstores. A pregnancy test detects a specific protein in urine called HCG, which is present in high amounts during pregnancy. If significant amounts of this protein are present, the test shows a positive result.

Pregnancy test showing positive result

For infectious diseases, these types of tests are often called “antibody tests.” When you contract a virus, your immune system will attack it, creating special proteins called antibodies in the process. These proteins bind to the virus so immune cells can locate and destroy it. The body creates unique antibodies for each pathogen it encounters, so they can be used as indicators of past or present infection. For example, if your blood contains antibodies to tuberculosis, you must have been exposed to tuberculosis at some point. These antibodies hang around in your system so that if you encounter the same disease again, your body is prepared to fight it off.

Compared to RNA tests, these kinds of antibody tests are fast and relatively simple, but they can produce false-negative results early in the disease course. For antibody tests to be effective, you need to have been sick long enough to produce the antibodies, otherwise the test will appear as a false-negative. In the setting of a pandemic, this can be particularly problematic, as false-negative results may prevent infected individuals from taking the proper isolation precautions. Furthermore, antibody tests can also give false-positive readings if you have already recovered from the infection, as the antibodies remain in your system long after symptoms resolve. Antibody tests to detect COVID-19 will likely use blood from a finger stick. The healthcare company Henry Schein has announced the availability of a new point of care antibody test that works on this principle. 

Finger with blood drop.

Nevertheless, antibody tests have a very important role to play in this pandemic. As more people recover after being sick, we will need to know who those people are because they will have developed some amount of immunity to the disease. They will likely be able to move freely through an infected population without becoming infected again. However, it is important to note that while this is true for many viral infections, it is not yet known if COVID-19 will behave exactly the same way. 

There is a second kind of antibody test that has the potential to work earlier in the course of the disease. These tests use antibodies to look for proteins on the outside of the viral envelope. We will call these viral-protein tests. For example, E25Bio, a Cambridge-based biotech company, has developed a POC test for COVID-19 that is currently being tested at Massachusetts General Hospital. The test resembles an over-the-counter pregnancy test, with one line vs two lines in the readout window. This new test, named the “Spike Dart,” can detect viral proteins in various bodily fluids, including mucus, saliva, blood and urine. The Spike Dart provides results in about 15 minutes. However, the tradeoff for quick results may be decreased sensitivity compared to the lab-based PCR assays, which is common for point-of-care tests. Nonetheless, this POC test may be a valuable tool in healthcare settings to rapidly isolate infected individuals for further testing and treatment. E25Bio has been in close contact with the FDA and hopes to attain emergency use authorization to deploy the Spike Dart in hospitals and doctors offices in the coming weeks. 

To summarize, there are three different types of tests in the news right now: RNA (nucleic acid) tests, antibody tests that look for antibodies against the virus in the blood, and viral protein-based tests that use antibodies to detect viral proteins. RNA tests are good at detecting new infections and monitoring how long a person is infected. Antibody blood tests can be more easily made portable to use in the field, but can only detect late-stage disease and past infections. Viral-protein POC tests are simple, fast, and inexpensive, but may operate at a lower sensitivity than lab-based testing.

This post was updated on 4/1/20 to include information about viral protein detection tests.

Additional Resources:

How Covid-19 Immunity Testing Can Help People Get Back to Work 

Coronavirus Testing Shouldn’t Be This Complicated

Abbott Point-of-Care Test

Current and Future Applications of Point-of-Care Testing – Centers for Disease Control

Example of Nucleic Acid Test for HIV Diagnostics – Video

Dr. Klapperich Welcomes You to the Blog

At my day job, I work on improving diagnostics for all kinds of diseases. These days that work is dominated by COVID-19. Some heroic members of my lab are still working on tests and test methods that might be helpful the next time this virus comes around.

About two years ago, I started writing a popular science book focused on medical devices and how they impact and intersect with women’s health. The work was slow, mainly because writing a book turns out to be hard.

To get my ass in gear and actually finish the book, last semester I hired three wonderful young women as research assistants. We had been meeting and chatting about this project weekly. Then COVID-19 hit us and now we are all working from home. A lot of our sci comm work has turned to the pandemic, and we decided that 280 character tweets don’t offer enough depth or permanency for the info we would like to share.

To keep this work going, Skylar, Sarita, and Lizy, and I have decided to share our (evidence based!) thoughts and some of our works in progress for the book here on the blog. You can learn a bit more about us here, but I can tell you, without exaggeration, these three women are the only reason this work can continue in this crazy time.

The scope of our writing project has expanded to include science and engineering explainers on more topics than just medical devices. I also guarantee that I will be injecting a lot of the personal into this blog. The first personal touches are the photographs. If they aren’t credited to someone else, they are my original art. -Cathie

Took this one with my Moment Macro lens at the 2017 Microfluidics GRC in Italy.