who works in a laboratory knows that there are certain rules and regulations to
be followed to ensure accuracy in testing, and the safety of both the patient
and testing personnel. With all the acronyms floating around (CLIA, FDA, CAP,
CMS, TJC) it can get confusing to keep track of who controls what, and which
rules apply to your specific lab. In the first installment of this 3-part
series on regulations, we’ll review the different federal agencies responsible
for oversight and moderation of the laboratory. In part 2 we’ll go further
in-depth to demystify testing complexity (waived, non-waived, PPM) and why it’s
important to know the correct classification for the tests you perform. Lastly,
we’ll review the optional accreditations available to labs, and how
accreditation differs from certification.
refers to the Clinical Laboratory Improvement Amendments of 1988. These
amendments were drafted to the Public Health Services Act, in which the federal
program was revised to include certification and oversight of clinical
laboratory testing. Although there have been two additional amendments made
after 1988 (1997, 2012), the law still continues to be cited as CLIA ’88 as it
is named within legislation.
CLIA regulations helped to establish quality standards for all U.S. laboratory
testing performed on human specimens (except for research) for the purpose of
assessment of health, or the diagnosis, prevention, or treatment of disease.
The regulations cover all aspects of testing including general laboratory
requirements, quality monitors, pre-analytics, analytic performance,
post-analytics, and personnel requirements.
addition to setting the basic ground rules for performing quality laboratory
testing, the CLIA regulations also require clinical laboratories to be
certified by their state as well as the Center for Medicare & Medicaid
Services (CMS) before accepting human samples for diagnostic testing.
Laboratories can obtain multiple types of CLIA certificates, based on the kinds
of diagnostic tests they perform. In order for laboratories to receive payments
from Medicare or Medicaid, laboratories must be properly certified for the
testing they are performing and billing for.
3 federal agencies responsible for enforcing the CLIA regulations: The Food
& Drug Administration (FDA), Center for Medicaid Services (CMS) and the
Center for Disease Control and Prevention (CDC). Each agency has a unique role
in assuring quality laboratory testing.
Centers for Medicare & Medicaid Services (CMS) is the federal agency
responsible for ensuring that the CLIA standards are upheld and enforced. Their
responsibilities include the following:
inspections and enforcing regulatory compliance
private accreditation organizations (such as CAP) for performing inspections,
and approves state exemptions
laboratory performance on Proficiency Testing (PT) and approving PT programs
CLIA rules and regulations
& Drug Administration (FDA) is primarily responsible for reviewing and
approving new tests, instruments, and equipment used in diagnostic laboratories.
They also perform the following tasks:
tests based on complexity
requests for Waiver by Application from manufacturers
rules/guidance for CLIA complexity categorization
for Disease Control and Prevention (CDC) responsibilities include the following
analysis, research, and technical assistance
technical standards and laboratory practice guidelines, including standards and
guidelines for cytology
laboratory quality improvement studies
proficiency testing practices
and distribute professional information and educational resources
the Clinical Laboratory Improvement Advisory Committee (CLIAC)
summarize, CLIA establishes the rules and guidelines that laboratories must
follow to ensure they are providing accurate laboratory results. Federal
agencies then work together to support the CLIA amendments and enforce
compliance. All certified laboratories will be subject to inspection by
regulatory agencies to ensure compliance with the rules. In some cases, your
local state Department of Health (DOH) or accrediting agency may be more
stringent or have additional requirements to be followed – always go with the
stricter requirement to ensure compliance with all agencies.
up next we’ll review how the FDA decides the complexity of each test, and how
this designation will affect the CLIA rules to be followed.
-Kyle Nevins, MS, MLS(ASCP)CM is one of ASCP’s
2018 Top 5 in the 40 Under Forty recognition program. She has worked in
the medical laboratory profession for over 18 years. In her current
position, she transitions between performing laboratory audits across
the entire Northwell Health System on Long Island, NY, consulting for
at-risk laboratories outside of Northwell Health, bringing laboratories
up to regulatory standards, and acting as supervisor and mentor in labs
with management gaps.
The general public doesn’t always know a lot about laboratory
testing in general, but most people know a little about blood types, even if
it’s what they have learned from TV! Blood types do seem to come up in casual
conversation. We might hear a conversation about blood type after someone has
donated blood, or between family members comparing notes, who ask “What’s your
type?” Yet, even with medical technologists, there can still be some confusion
about blood types and blood typing, particularly if one has not worked in Blood
Bank in many years. I recently received an email from a colleague who had a few
questions about blood types, as she has not worked in Blood Bank for over 40
years. I always tell my students that no question is a bad question, and indeed,
she asked some very good questions, which I will address with this case study.
What blood type is listed on a patient’s chart if they type “O
What blood type is recorded on a donated unit of blood typed “O
What type of blood does an “O Du” patient receive?
Can an “O Du” patient have a transfusion reaction if they are
transfused with O positive blood? Would she need to receive O negative blood in
Does an “O Du” patient need to receive RhoGAM if she pregnant and
her husband is Rh positive?
If you have ever wondered or can’t remember details about any of
these questions, you’re in the right place. So, what’s new, if anything, with
Landsteiner discovered the ABO blood group system in 1901, and
identified A, B and O blood types, using experiments performed on blood from
coworkers in his laboratory. The discovery of the codominant AB blood type soon
followed, but it was not until around 1940 that the Rh blood group was first described.
In 1946, Coombs and coworkers described the use of the antihuman globulin (AHG)
to identify weak forms of Rh antibodies in serum. For us old blood bankers, the
original name for this test was the Coombs’ test. (You will still find
physicians ordering a Coombs’ test!) The current and proper name for this is
the direct antibody test (DAT), which is used to detect in vivo sensitization
of RBCs. AHG can also be used to detect in- vitro sensitization of RBCs using
the 2 stage indirect antibody test (IAT).
Since Landsteiner’s work, we have not discovered any new blood groups
that are part of the routine blood type. The ABO and Rh blood groups are still
the most significant in transfusion medicine, and are the only groups consistently
reported. However, we currently recognize 346 RBC antigens in 36 systems.1 Serological tests determine RBC
phenotypes. Yet, today we can also determine genotype with family studies or
molecular testing. This case study and 2 part blog reviews some terminology in
phenotyping, some difficulties and differences encountered, and explores the
possibility of RHD genotyping to assess a patient’s true D status.
Our case study involves a 31 year old woman who is newly married.
She is not currently pregnant, has never been pregnant, is not scheduled for
surgery but has had a prior surgery 15 years ago, and has never received any
blood products. She and her husband recently donated blood and, as first time
blood donors, just got their American Red Cross (ARC) blood donor cards in the
mail. The husband noted that his card says that he is type O pos. The woman
opens her card, and, with a puzzled look on her face, says “My card says I’m an
O Pos, too. There must be a mistake.” She knows she has been typed before and
checks her MyChart online. Sure enough, her blood type performed at a local
hospital is listed in her online MyChart as O negative. She further checks
older printed records and discovers that 15 years ago, before surgery, she was
typed at a different hospital as “O Du”. She is very upset, wondering how she
can have 3 different blood types. She is additionally concerned because they
are planning to have children and recalls being told that because she is Rh
negative, that she would need Rhogam. Is she Rh negative or positive, and what
does Du mean? Will she need Rhogam when pregnant? She has many questions and calls
the ARC donor center for an explanation.
What blood type is listed on a patient’s chart
if they type “O Du”?
What is happening here, what is this woman’s actual blood type, and what testing can be done to ensure accuracy in Rh typing? From the patient reports, it appears that this woman has what today we call a “weak D.” Du is an older terminology that should no longer be used, and that has been replaced by the term “weak D.” But, why does she have records that show her to be an O neg, a type O, Du (today, this would be written O weak D), and now, a card from ARC stating she is O pos?
RhD negative phenotypes are ones that
lack detectable D antigen. The most common Rh negative phenotype results from
the complete deletion of the RHD gene. Serologic testing with anti-D is usually
expected to produce a strong 3+ to 4+ reaction. A patient with a negative
anti-D at IS and at IAT would be Rh negative. If the patient has less than 2+ strong
reaction at immediate spin (IS), but reacts at IAT, they would be said to have
a serologically weak D.1 Historically, weak D red blood cells (RBCs)
are defined as having decreased D antigen levels which require the IAT for
detection. Today’s reagents can detect many weak D
types that may have been missed in the past, without the need for IAT. However,
sometimes IAT is still necessary to detect a weak D. When this is necessary is
dependent on lab SOPs and whether this is donor testing or patient testing. The
reported blood type of this patient also depends on the SOPs of the laboratory
that does the testing. And, the terminology used for reporting is also lab
dependent. It is not required by AABB to test patient samples for weak D
(except for babies of a mother who is D negative). There is also no general
consensus as to the terminology to be used in reporting a weak D. Some labs would
result this patient as O negative, weak D pos. Some labs may result O pos, weak
D pos. Others may show the individual reactions but the resulted type would be
O pos. Labs who do not perform weak D testing would report this patient as O, Rh
negative. The following chart explains why this patient appears to have 3 types
What blood type is recorded on a donated unit
of blood typed “O Du?”
AABB Standards for Blood Banks and
Transfusion Services requires all donor blood to be tested using a method that
is designed to detect weak D. This can be met through IAT testing or another
method that detects weak D. If the test is positive, the unit must be labeled
Rh positive. This is an important step to prevent alloimmunization in a
recipient because weak D RBCs can cause the production of anti-D in the
recipient. This also explains why the ARC donor card this patient received
lists her type as O pos.
of blood does an “O Du” patient receive?
Historically, weak D red blood cells
(RBCs) were defined as having decreased D antigen levels which require the IAT
for detection. A patient who is serologic weak D has the D antigen, just in
fewer numbers. This type of weak D expression primarily results from
single-point mutation in the RHD gene that encodes for a single amino acid
change. The amino acid change causes a reduced number of D antigen sites on the
RBCs. Today we know more about D antigen expression because we have the
availability to genotype these weak D RBCs. More than 84 weak D types have been
identified, but types 1, 2, and 3 represent more than 90% of all weak D types
in people of European ethnicity.2 An Rh negative patient has no D
antigen and should, under normal circumstances, only receive Rh negative blood.
Yet, there has been a long history of transfusing weak D patients with Rh
positive RBCs. 90% of weak D patients genotype as Type 1, 2 or 3 and may
receive Rh positive transfusions because they rarely make anti-D. 2
It is now known that weak D can actually
arise from several mechanisms including quantitative, as described above, position
effect, and partial D antigen. Molecular testing would be needed to
differentiate the types, but, with the position effect, the D antigen is
complete and therefore the patient may receive Rh positive blood with no
adverse effects. On the other hand, a partial D patient may type serologically
as Rh negative or Rh positive and can be classified with molecular testing. It
is important to note that these partial D patients are usually only discovered
because they are producing anti-D. If anti-D is found, the patient should
receive Rh negative blood for any future transfusions.
Thus, 3 scenarios can come from typing
the same patient. With a negative antibody screen, and because 90% of weak D
patients have been found to be Type 1, 2 or 3 when genotyped, many labs do not routinely
genotype patients and will report the blood type as Rh pos and transfuse Rh pos
products. However, depending on the lab medical director and the lab’s SOPs,
these same patients may be labeled Rh neg, weak D and receive Rh negative
products. There is no general consensus on the handling and testing of weak D
samples. The 3rd scenario is that many labs do not test for weak D
in patients at all, and a negative D typing at IS would result in reporting the
patient as Rh neg, with no further testing. In this case, the patient would be
transfused with Rh negative products.
Can an “O
Du” patient have a transfusion reaction if they are transfused with O positive
blood? Would she need to receive O negative blood in a transfusion?
This question was covered
somewhat in the above discussion. Policies regarding the selection of blood for
transfusion are lab dependent, dictated by the lab medical director, and are
based on the patient population, risk of developing anti-D, and the
availability or lack of availability of Rh negative blood products. Anti-D is
very immunogenic. Less than 1 ml of Rh pos blood transfused to an Rh negative
person can stimulate the production of anti-D. However, not all patients
transfused with Rh positive blood will make and anti-D. As discussed above, 90%
of weak D patients are types 1, 2 or 3, would be unlikely to become
alloimmunized to anti-D. If a weak D patient with a negative antibody screen
receives a unit of D pos RBCs, there is a very small possibility that they are
a genotype who could become alloimmunized to the D antigen and produce anti-D. However,
as stated above, the majority of weak D patients can be
transfused with D positive RBCs. Thus, with few exceptions, from a historical
perspective, one can safely classify the weak D as D positive.
This question gets a little trickier
when dealing with females of childbearing age. We particularly want to avoid
giving Rh positive blood to females to avoid anti-D and the complications of
Hemolytic Disease of the Fetus and Newborn. Therefore, when dealing with these
patients, lab policies and physicians tend to be more conservative in their
approach to transfusion. The consequences, however, in males and older females
are less serious and these patients could be given Rh positive blood if there
exists a shortage of Rh negative units. Any patient who becomes alloimmunized
to the D antigen, would thereafter be transfused with Rh negative products.
Does an “O
Du” patient need to receive RhoGAM if she pregnant and her husband is Rh
This, again, would be up to the medical
director, the lab’s SOPs or the patient’s physician. Depending on lab practice,
the lab may or may not perform weak D testing. If the lab does not perform weak
D and results this patient as Rh neg, the patient would get Rhogam. If the lab
does do weak D testing and finds a weak D phenotype, the decision whether or
not to give Rhogam would be up to lab practices and the practitioners involved.
The lab’s policy on terminology used in resulting the type may also reflect the
decision whether or not to give Rhogam. This brings up a lot of questions in
the lab because we know that a patient who would not make anti-D would not need
Rhogam. So, what is the best course of action? Read my next blog to learn more
about troubleshooting and resolving D typing discrepancies!
From the discrepancies in reported type in this individual, and putting all the pieces of the puzzle together, we can conclude that this patient is a weak D phenotype. However, the type reported and the terminology used varies from lab to lab. Molecular testing is available, yet most labs are still using serological testing for blood types for both donors and patients. This is based on several factors within the lab setting. Stay tuned for my next Blood Bank blog exploring D typing discrepancies and the financial aspects of performing genotype on pregnant patients to clarify Rh type.
-Becky Socha, MS, MLS(ASCP)CM BB CM graduated
from Merrimack College in N. Andover, Massachusetts with a BS in
Medical Technology and completed her MS in Clinical Laboratory Sciences
at the University of Massachusetts, Lowell. She has worked as a Medical
Technologist for over 30 years. She’s worked in all areas of the
clinical laboratory, but has a special interest in Hematology and Blood
Banking. When she’s not busy being a mad scientist, she can be found
outside riding her bicycle.
A 15 year old male with a past medical history significant
for Tetralogy of Fallot (congenital heart defect), multiple valve replacements,
chronic kidney disease, and prior Bartonella endocarditis. He presented with a
“flu-like” illness including muscle aches, fevers, fatigue, and night sweats. His
symptoms slowly dissipated after about three days. However, he had labs drawn
including multiple blood culture sets which were all positive for growth.
Gram stain showed gram positive bacilli and culture plates
grew two morphologies of slow growing gray, granular and opaque colonies.This organism was identified by
genus Corynebacterium comprises a
collection of irregular-formed, rod-shaped or coccoid bacteria that are
non-motile, catalase-positive, and non-spore-forming.
(previously designated as Corynebacterium
hofmannii) is a nonlipophilic, nonfermentive, urease- and nitrate-positive Corynebacterium species.1C. pseudodiphtheriticum is part of the
usual oropharyngeal bacterial flora, including the nares and throat. It appears
to play a role in preventing colonization of oropharyngeal epithelia by
commonly, C. pseduodiptheriticum is a
pathogen of the respiratory tract with cases of nosocomial and
community-acquired pneumonia, bronchitis, tracheitis, pharyngitis, and
rhinosinusitis. Endocarditis is the second most common infection site, although
very rare. Cases of urinary tract and wound infections have also been reported.
is usually with penicillin alone or in combination with aminoglycosides. Antibiotic
susceptibility profiling of C.
pseudodiphtheriticum isolates showed that resistance to oxacillin,
erythromycin, clindamycin, and macrolides are common.1
Large biological and chemical spills are not a common
occurrence in the laboratory. That’s a good thing, but when they do occur, they
can create a very dangerous situation. It is vital that lab staff know how to handle
such events even though they may not be commonplace.
Some laboratories differentiate between large and small
spills. They may have an emergency number to call for a hazardous spill
response team. Other smaller facilities simply don’t have that in place. Either
way, it’s important for laboratory professionals to know they are the experts
about the biological and chemical materials they use, and they need to be in
charge as the experts when a spill situation needs to be managed.
Most laboratory spills can be managed using a standardized step-wise
process known as the S.P.I.L.L.E.D. procedure. I don’t usually ask lab staff to
memorize the acronym, but having the information contained on a poster with the
lab spill kits can make a clean-up procedure go smoothly.
S = Secure the Site – Make sure no one walks through the
area where a spill has occurred. It could be a dangerous situation if a
hazardous chemical is spilled, and you would never want someone slipping in the
area or tracking the spilled material to another area.
P = Protect Yourself – Arm yourself with the
appropriate Personal Protective Equipment (PPE). In a lab spill event, this
would mean using a lab coat, gloves, and face protection to prevent accidental splashes.
I = Inspect the Spill – Look to see what was spilled.
If it is a hazardous chemical, is there a concern about fumes? Obtain a Safety
Data Sheet to see if section 6 will give any special information about handling
the accidental release or spill of that chemical. Consider other spill concerns
such as broken glass or possible ignition sources if flammable material is
L = Lay Down a Barrier – If the spill is large and
spreading, lay down spill pillows or booms designed to contain a flow of
liquids. Surround the spill area with these materials. Sometimes, the use of an
emergency shower can create the need for a barrier to be made.
L = Lay Down Absorbents – No matter the size of the spill,
the next step is to place any absorbent powders, granules or clean-up pads to
soak up the spilled material. If the absorbent is also a neutralizer, make sure
you allow the necessary time for neutralization to occur.
E = Extract the Mess – Use implements to pick up the
materials used for stopping and absorbing the spill.
D = Dispose of the Waste – Properly dispose of all
materials involved with the spill clean-up. If there was glass involved, be sure
to use a sharps container. Biohazard
material should go into an appropriate container, and chemical waste materials
may need to be disposed of separately for pick-up by a chemical waste vendor.
Lab staff should be able to access spill control materials
quickly, and the necessary items should be stored in a location designated by
signage. Perform an inventory of spill supplies and make sure there are
adequate materials that could handle spills of the biohazards and chemicals stored
and used in the department. Be sure items in the spill kit are not expired, and
if there is no expiration date for absorbent powders, check them at least
annually for effectiveness.
All laboratory staff need to have complete spill clean-up
training. Give information about the types and locations of spill kits and how
to handle various types of spills that can occur. Once that training is done,
it will become important to perform spill drills in the department. Drills can
be performed a number of different ways, but a common method involves having a “victim”
spill water onto the floor and claim the material splashed into their eyes.
Watch from a distance to see how the staff reacts. Do they provide appropriate
first aid? Do they inspect the container label? Do they access the correct
clean-up supplies and facilitate cleaning efficiently? Make notes of how the
drill went, discuss them with the staff, and repeat the drills until all staff
are comfortable with a spill situation.
and chemical spills should not be a common occurrence in the lab. When they do
occur, however, the situation can become serious quickly, and a fast and effective
clean-up needs to occur. Because these events are rare, it becomes important to
provide regular spill training and drills so staff can remain ever-ready to
–Dan Scungio, MT(ASCP), SLS, CQA (ASQ) has over 25 years
experience as a certified medical technologist. Today he is the
Laboratory Safety Officer for Sentara Healthcare, a system of seven
hospitals and over 20 laboratories and draw sites in the Tidewater area
of Virginia. He is also known as Dan the Lab Safety Man, a lab safety consultant, educator, and trainer.
I don’t think anyone enjoys filling out
the paperwork at a doctor’s office. For transgender individuals, this can be an
experience that ranges from irksome to offensive. Most intake forms don’t allow
for expression of their gender identity. Furthermore, confusion on gender and
sex can create real confusion and healthcare failures in several places that
laboratory medicine encounters a transgender individual.
Arguably the first place the lab
encounters a transgender patient is via the phlebotomist. These professional
collectors of blood must confirm two patient identifiers, which are often name
and date of birth. The “name” used is the legal name. Using a transgender
person’s “dead name” (name given at birth) represents a gender they do not want
to be associated with and can be a very offensive experience. “Isn’t it obvious
that name is not what I look like?”
While names can be legally changed, this
happens with varying difficulty and legal cost in different states. A solution
is to improve training of phlebotomists to explain the necessity of confirming
a legal name so lab results are properly matched to the patient. Additionally,
front-desk intake workers should be similarly trained to interact with
transgender patients when recording demographic information. This can be aided
by electronic health records (EHR) becoming more flexible and inclusive of the
Traditionally, EHR would only include one
field for SEX: M or F.
Several in the laboratory community have
asked how many different gender options should be included? Facebook included
up to 71 options in 2017. That’s a big step up from the 2 traditional EHRs are
The World Professional Association for
Transgender Health (WPATH) executive committee in 2011 outlined the recommended
fields to include in EHR: preferred name, sex assigned at birth, gender, and
pronoun preference. EHRs are evolving and can be flexible depending on the user
requirements. At my program, we use EPIC at 3 different different sites (children’s,
county and university hospitals) and each has a different version.
From what I’ve seen preferred name is an easy addition and would not interfere with
functions of the EHR or Laboratory Information Systems (LIS), which is the
Lab’s version of EHR.
If the field for sex assigned at birth is different from gender, then it would clear up any confusion about whether the
person is transgender and then they should be addressed by the pronouns
matching the gender. While there is a spectrum of genders, only transgender males
and transgender females are of a high enough prevalence to have medically
relevant recommendations. Plus, if a system at least starts here, they could
expand further as necessitated by their population.
EHR could include preferred pronouns, but I haven’t seen this implemented in an EHR
yet. Ideally, you would just use the pronouns that match the intended
appearance of the individual (ma’am to someone wearing a dress, etc.).
Lastly, I think Legal sex should be added to the EHR as well. One of our hospitals
has this and it makes several processes easier such as processing hormone
Legal (or administrative) sex, sex assigned at birth, and gender data fields provide the clearest and simplest picture of a patient
and should be a minimum for labs making recommendations for changes to HER.
Next month I will describe in greater
detail the issues that can arise in the lab when gender or sex are entered
incorrectly in the system for transgender patients and how this can negatively
affect care delivery.
Deutsch MB, Green J, Keatley J, Mayer G, Hastings J, Hall AM, World Professional Association for Transgender Health EMR Working Group. Electronic medical records and the transgender patient: recommendations from the World Professional Association for Transgender Health EMR Working Group. J Am Med Inform Assoc. 2013 Jul-Aug; 20(4):700-3.
Gupta S, Imborek KL, Krasowski MD. Challenges in Transgender Healthcare: The Pathology Perspective. Lab Med. 2016 Aug; 47(3):180-188.
-Jeff SoRelle, MD is a Chief Resident of Pathology at the University of Texas Southwestern Medical Center in Dallas, TX. His clinical research interests include understanding how the lab intersects with transgender healthcare and improving genetic variant interpretation.
I merrily wait in line at Starbucks for my iced
cappuccino with soy milk, pay $5+ for $0.25 worth of goods poured into my
$14.00 souvenir mug, and walk out the door with my head held high, joyous with
the privileges of conspicuous consumption. My server was super-cheery and the
brief exchange we had was so pleasant—they really love me! I need that high because I am off to the
Department of Motor Vehicles (DMV) for a driving-related task and know–just
know–that there will be an incredibly long line at the end of which sits a
disgruntled government employee who doesn’t care if I show up or not. Their
motivation to help us is non-existent. “Why would anyone ever work here?” I
ask, sipping my delicious beverage.
Today, a doctor called someone in the United
States (US) and told them the biopsy taken from their leg earlier this week has
come back as invasive cancer. A bit distraught and nervous, the patient called
up a nationally recognized cancer center, from which they only live a few
miles, and on the end of the line is a caring, pleasant voice who informs them they
can be seen today! The valet parking is gorgeous, the building is gleaming with
glass and steel, and every face they see as they journey from check-in to
clinic is smiling, compassionate, and sincere. Their nurse and then doctor are
both genuine people with their patient’s best interest in mind, and they
carefully and completely explain what has been found, what needs to be done, and
how they are going to get through all of this together. As they depart, the
receptionist grabs them for a brief moment to return their private insurance
card and waves at them as they depart, adding, “We will see you soon!”
Today, someone in Africa went back to the hospital—an
8-hour journey from their home—where their biopsy was performed a month ago,
hoping to get the result. After several people searched multiple offices and
inquired with several people, the result is found and brought to them, a single
piece of paper. Payment is required before they can receive the biopsy results.
They have brought money with them, which they gathered from three neighbors, their
brother, and by selling some chickens, and pays for the report. They read the
report and, at the bottom, notices that it says additional testing is needed.
Confused, they ask for help and a pathologist comes to find them. Respectfully,
the pathologist explains that additional testing is needed, which is not
available in the hospital despite the pathologist’s strong desire to have it,
but they can send the biopsy to a lab elsewhere to do the testing which will
cost about 3 times what they just paid for the primary report. They happen to
have enough and pay the amount requested. The report will be back in about a
month. Two months later, they have returned to the hospital for the 4th time
and the report is now available. The testing that was done simply confirms that
the primary diagnosis is accurate. They go to the oncology clinic on the same
campus and sit in the waiting area with 3 dozen other people. They sleep at the
clinic overnight outside with about a dozen people. The following afternoon, they
are finally seen and the oncologist reviews the report. He notes that if the
patient had come to the clinic as soon as they had the biopsy result three
months ago, a simple surgery would have cured them of this lesion. But now,
because they waited so long, there is only chemotherapy available which is
expensive and, the oncologist reports, doesn’t actually work very well for this
Before you shed a tear for this terrible situation
(while I sip my cappuccino and a nurse begins someone’s chemotherapy in a
shiny, brightly lit, and expansively windowed infusion unit not far away), we
have to ask ourselves what is really going on? First and foremost, this is an
allegory to make a few points but the situation is repeated over and over again
every day in the US and Africa. However, as a simple, superficial explanation,
the person with cancer in the US is receiving their cancer therapy from
Starbucks and the person in Africa had to go to the DMV.
Cancer care in the United States is almost
entirely in the private sector, dispersed among the 1500 cancer treatment
facilities, of which 70 are comprehensive cancer centers.[i]
Based on the US population, the expected cancer rate, 100% detection, and 240
working days for a given cancer center, there are on average only 5 new
patients per day per cancer center. Is that why one can often get that appointment
right away in a major cancer center or is it really a concierge customer
service effort? A standard private insurance plan for which I pay, for example,
$250 per month and my employer pays $1300 per month is accepted by cancer
centers and results in small co-pays for multiple appointments, which can be
covered with a Flexible Spending Account (FSA) or Health Savings Account (HSA).
On insurance statements after appointments, some of the services received cost
thousands of dollars but the patient portion was only, say, a hundred dollars,
again, which may be paid with FSA/HSA. It’s so great that we have insurance
because the insurance company is bearing the brunt of costs. But are they?
In the United States, 79% of facilities providing
health care are private, a mix of non-profit and for-profit.[ii]
But 64% of all healthcare in the United States is paid for by the US government
through Medicare, Medicaid, the Veterans Administration (VA) system, and Children’s
Health Insurance Program (CHIP).[iii],[iv]Since
almost every cancer care facility is private (or, stated another way, “not
free”), that means that for every one of us at the cancer center getting
treatment, for which we and our employer are paying through insurance, there
are two people getting the same treatment at the same high-level quality of
care for which the government is paying. Those other deductions from our
paychecks for Medicare and Medicaid (which everyone pays, regardless of how
old, as long as they are employed and regardless of their own health insurance
plan) are going towards the 64% coverage. The point is not that the US
healthcare system is expensive. The
point is that there is a lot of revenue and resource being put into the
healthcare system and, thus, there is a high-quality product or experience that
If we look at any low GINI index country and
compare their GDP with the US GPD and compare their spending on healthcare as a
% of GDP, we don’t even need to do the math to see that there is very little
money per person available in the system for any type of healthcare. The
challenge in low-resourced settings (by which it is meant low-resourced
patients in low-resources locations) is both a lack of funding available to
provide healthcare services along with a lack of “stuff” to provide those
services. We can invoke the law of supply and demand to try and argue that the
people can rise up and demand more healthcare facilities and “someone” will
meet that supply. In the US, this results in the Starbucks model. In a
low-resourced setting who has the incentive to meet that supply? Where does the
government get the money from to create such a system? What private corporation
is going to start a healthcare program that provides universal coverage
regardless of what you can pay?
The answer is really quite simple. This model of
healthcare is insufficient for cancer and isn’t going to work for all patients.
Moreover, the Starbucks model is not really applicable, sustainable, nor
equitable. When we go to Starbucks for their coffee, to some degree, our choice
of Starbucks is because of the a) flavor of the coffee, b) cost of the coffee,
c) perception of the coffee, and/or d) convenience of the coffee. We could
always choose Dunkin’, Peet’s, Tim Horton’s (maybe let’s not go there for this
analogy), or Green Mountain coffee at a different location. There is variation
in pricing and convenience. There is variation in the condiments we can use to
doctor our coffee. An economy and series of markets exist which allow Starbucks
to gather resources from dozens of other companies to provide your coffee. But,
ultimately, we are all buying coffee which has caffeine which has a desired
effect. We can go to a free AA meeting or to a soup kitchen and get some pretty
basic coffee if we don’t have the money to pay. The point is we have choices
and we can pay a high price, a low price, or no price and we get coffee.
The Starbucks model does work for a certain sector
of the population but not everyone. Since vast majority of cancer care in the
US is private, the Starbucks model falls down because we don’t actually have
any free options as a society and “low-cost healthcare” is not typically
appealing to most Americans with cancer because they have their mortality at
stake (no one wants cancer nor does anyone want to die from cancer). In fact,
desperation in the face of cancer is what makes the US one of the only places
in the developed world where people go bankrupt trying to be treated for
cancer. The ultimate inequity is that cancer care is “pay to play” in the US
and there essentially aren’t safety nets for any populations that can’t pay
(homeless) or are living below a certain income threshold (i.e., the ~10% of
Americans without healthcare plus a large percentage with insufficient
Please remember, these are human beings and they
didn’t choose to get cancer (there is no demand for cancer… there is only
demand for cancer care!). Since they didn’t have a choice in the disease they
have to be burdened with, why is there an expectation that they should pay for
the treatment? Moreover, if a patient has a stage I cancer, easily surgically
removed and cured vs. a Stage III cancer requiring months of various therapies
at a very high cost, how do we ethically explain an increased cost for a worst
state of disease? It’s really an inverse quality spectrum and we make patients
pay more for getting a lot less. We pay for insurance in case we ever do get
cancer (or other major disease). It’s a risk reduction or risk aversion
pre-payment. Like we do with our car or our house or our boat. Those last three
things we choose to have (and are luxuries). We don’t get to choose to have
health. It’s just an inherent part of being human so holding someone
accountable for it because they didn’t have the resources to “prepare for the
worst” is really the wrong attitude. Our healthcare system isn’t perfect but
there are gaps that could be easily filled if resources are allocated
efficiently to meet the whole populations needs—that’s the benefit of having a
large resource supply into the system. We just have to find the operational
efficiency to make the costs work.
However, when we remove the luxuries of insurance, Medicare, and Medicaid and other payments systems from the health sector or, worse, simply assume the government’s role is to provide healthcare 100% free to all citizens in a resource-limited or resource-constrained setting, we suddenly have an untenable situation. The economy and tax-base are not there to create the resources. We find overworked, underpaid, and undersupplied medical staff working in crowded conditions. For single entity care (e.g., HIV, tuberculosis, malaria), vertical programs have made great strides in combatting these diseases even in some of the poorest countries in the world. But cancer is anything but simple with the complexity of cross-discipline collaboration, spectrum of disease, range of treatments, and inherent costs creating huge gaps in the delivery of cancer care. Economic and physical infrastructure for the provision of care is what is needed to meet this challenge. Our current Starbucks model in the US would be extremely difficult to replicate in a low-resourced setting due to the lack of infrastructure. However, when this infrastructure is assessed, planned for, and implemented, cancer care can be delivered in these settings at a significantly lower cost per patient. Adding infrastructure implementation high-quality private facilities and public-private partnerships creates a way forward to pump resources into the system and insure that no patient is left behind. To round out this allegory, AAA locations (a commercial car-servicing company) in various parts of the US allow one to renew your driver’s license with them, rather than the DMV. I did this once, it was VERY fast, friendly, and efficient. This type of public-private partnership worked for me and I believe it will work for cancer if we are willing to try.
[ii] “Fast Facts on US Hospitals”.
Aha.org. Retrieved December 1, 2016.
Himmelstein DU, Woolhandler S (March 2016). “The Current and Projected
Taxpayer Shares of US Health Costs”. American Journal of Public Health.
106 (3): 449–52. doi:10.2105/AJPH.2015.302997. PMC 4880216. PMID 26794173.
Government’s share of overall health spending was 64% of national health
expenditures in 2013
Leonard K (January 22, 2016). “Could Universal Health Care Save U.S.
Taxpayers Money?”. U.S. News & World Report. Retrieved July 12, 2016.
-Dan Milner, MD, MSc, spent 10 years at Harvard where he taught
pathology, microbiology, and infectious disease. He began working in
Africa in 1997 as a medical student and has built an international
reputation as an expert in cerebral malaria. In his current role as
Chief Medical officer of ASCP, he leads all PEPFAR activities as well as
the Partners for Cancer Diagnosis and Treatment in Africa Initiative.
We have reviewed from start to
finish the next generation sequencing wet bench process, data review and
troubleshooting. I’d like to take a more
in-depth look at the types of variants that can be detected by the targeted
amplicon NGS panels that our lab performs:
single nucleotide variants, multi-allelic variants, multi-nucleotide
variants, insertions (including duplications), deletions and complex indels. In our lab, we review every significant
variant and variant of unknown significance in IGV to confirm the call is made
correctly in the variant caller due to the difficult nature of some of these
variants. I have included screenshots of
the IGV windows of each of these types of variants, to show what we see when we
Single Nucleotide Variants (SNV)
The most common (and straight forward) type of variant is a single nucleotide variant – one base pair is changed to another, such as KRAS c.35G>A, p.G12D (shown below in reverse):
A multi-allelic variant has more than one change as a single
base pair (see below – NRAS c.35G>A, p.G12D, and
c.35G>C, p.G12A – shown below in reverse). This may be the rarest type of variant – in
our lab, we have maybe seen this type in only a handful of cases over the last
four years. This could be an indication
of several clones, or different variants occurring over a period of time.
Multi-nucleotide Variants (MNV)
Multi-nucleotide variants are variants that include more
than one nucleotide at a time and are adjacent.
A common example is BRAF p.V600K (see below – in reverse) that can occur
in melanoma. Two adjacent nucleotides
are changed in the same allele. These
variants demonstrate one advantage NGS has over dideoxy (Sanger) sequencing. In dideoxy sequencing, we can see the two
base pair change, but we cannot be certain they are occurring on the same
allele. This is an important distinction
because if they occurred on the same allele, they probably occurred at the same
time, whereas, if they are on different alleles, they were probably two
separate events. It is important to know
for nomenclature as well – if they are on the same allele, it is listed as one
event, as shown below (c.1798_1799delGTinsAA, p.V600K) as opposed to two separate
mutations (c.1798G>A, p.V600M and c.1799T>A, p.V600E). As you can see in the IGV window below, both
happen on one strand.
Insertions are an addition of nucleotides to the original
sequence. Duplications are a specific
type of insertion where a region of the gene is copied and inserted right after
the original copy. These can be in-frame
or frameshift. If they are a replicate
of three base pairs, the insertion will move the original sequence down, but
the amino acids downstream will not be affected, so the frame stays the
same. If they are not a replicate of
three base pairs, the frame will be changed, causing all of the downstream
amino acids to be changed, so it causes a frameshift. A common example of a frameshift insertion is
the 4bp insertion in NPM1 (c.863_864insCTTG, p.W288fs)
that occurs in AML. In IGV, these are
displayed by a purple hash that will show the sequence when you hover over it.
Deletions, on the other hand, are when base pairs are
deleted from the sequence. These can be
in-frame or frameshift, as well. An
example is the 52bp deletion (c.1099_1150del, p. L367fs) found in the CALR
gene in cases of primary myelofibrosis or essential thrombocythemia.
Lastly, NGS can detect complex indels. These, again, are a type of variant that we
could not distinguish for sure using dideoxy sequencing. We would be able to detect the changes, but
not whether or not they were occurring on the same strand, indicating the changes
occurred at the same time. The first
example is a deletion followed by a single nucleotide change – since these both
occur on the same strand, they most likely occurred together, so they are
called one complex deletion/insertion event (KIT c. 1253_1256delACGAinsC, p. Y418_D419delinsS). First the ACGA was deleted, then a C was
The last example involves multiple nucleotides changes all
in the same vicinity (IGV is in reverse for this specimen as well). Using HGVS nomenclature as in all the
previous examples, this would be named RUNX1 c.327_332delCAAGACinsTGGGGT,
-Sharleen Rapp, BS, MB (ASCP)CM is a Molecular Diagnostics Coordinator in the Molecular Diagnostics Laboratory at Nebraska Medicine.