Research Corner
Natural Histories and Registries:
the good, the bad and the oiy.
Kimberly A Chapman, MD, PhD
Children’s National Rare Disease Institute, Washington D.C.
kchapman@childrensnational.org
Children’s National Rare Disease Institute, Washington D.C.
kchapman@childrensnational.org
So you are thinking in enrolling yourself or your care into a research study, thank you for helping us
understand your family’s disorder. We are going to start a new section to the newsletter to talk about
research.
Let’s start with what research is. It is a system or process in which the goal is to better understand
something in the world around us. We divide research into clinical (that which affects the patient
directly) and basic (that which studies fundamental processes, e.g. studying the Kreb’s cycle or how
cells talk to each other). Today we are going to talk about a subset of clinical research. As part of this
discussion, we are going to examine the expected benefits and risks from this subset of clinical
research--observational studies.
The two big, most basic categories of clinical research, basically research that which is designed to
understand the natural course of a disorder (observational) and that which tries to impact that natural
course (interventional). Sometimes, the research protocol tries to do both, especially if little is known
about a particular disorder or if a disorder is generally lethal to almost all with the disorder.
So from this point forward, we are going to ignore issues of interventional studies—these are clinical
trials in which an intervention, like a medication or a device is tested to see if it works better than
current practice and address these at a future date, and focus on observational studies.
Observation studies have several flavors, the shallow, the medium and the deep evaluations. In
general, observational studies collect information about an individual (like an individual with an
organic acidemia and their family). They can collect information at one particular time in many
individuals or can follow an individual or cohort of individuals over time. The best designed studies to
gather natural history—what happens in the disorder with current interventions over time---follows
individuals through time, but these can take a long time so some studies are designed to look at many
individuals who are at different points in their disorder at one moment in time and makes assumptions
about impact of time on the disorders. Either of these studies can be shallow, medium or deep in
terms of how much information they gather.
A study which is designed to take a shallow look at a disorder looks for the most basic facts (i.e.
disorder, genotype, current health) and often is fairly short in length (and so can take less time to
complete the initial forms). This can gather information once or over time from the same individuals.
The benefit from this study is that it can provide a “google earth” view of the disorder and takes little
time from each participant to gather the information (like minutes). The problem is it is a shallow
look at the disorder and so rare complications or occurrences are unlikely to be identified.
A study which is more in depth (a deep information study) tries to examine every possible thing about
a disorder and collects a lot of data on each participant often over the course of days. Often times this
type of study also gathers biological specimens (i.e. laboratory, biopsy, etc.) and radiological data (i.e.
X-ray, MRIs, etc.). Dr. Venditti’s natural history studies (for MMA and PA) at NIH are an example of
this type of study. Again individual participants can be studied over time (like Dr. Venditti’s studies) or
deeply once. This is like getting a magnifying glass out on a walk through the neighborhood and
studying as much as possible as closely as possible. You learn lots about lots of things but it takes lots
of time and produces much data. The benefits with these studies is rare occurrences or small changes
are more likely to be identified. The disadvantage is it takes lots of time from the participant and is
very expensive for the researcher.
The type of study which sits between these two in the continuum of studies is the medium study. It is
like the view one has walking down the street in one’s neighborhood, some detail (the designs on the
houses), but not lots of specifics (no idea how many ants on the sidewalk). Our natural history
registry with NORD is an example of this type of study. It does not gather as much information as the
deep study, but more than a shallow study. It tries to gather enough information that common rare
occurrences can be identified, but has less time commitment (more measured in an hours).
Each of these observation studies have some risks. Consent to participate in research of this type
should include a list of the risks identified and possible mitigations for these risk.
Privacy and confidentiality are two of the biggest risks with observational studies. Those observational
studies which include laboratory and radiology as a component also have risk associated with these
procedures.
Some common privacy risks in these types of studies include 1) how safe are my data and will
someone outside the study be able to see them and identify that it belongs to me, 2) can I be
identified by my data and how are my data being protected? Data here can mean your name, your
address, connecting the disorder to you, your health history, your date of birth, etc. You can
understand why these privacy issues could be concerning and why you as a participant (or your care)
should be aware of this risk.
Most reputable registries and natural history studies tell you how and where your information is stored
and protected as part of the consent. They are aware of the concern. In fact, the European Union
has just required much more strict privacy rules for any registry or natural history study which has
anyone who is lives in the EU or storage in the EU (it is called the General Data Protection
Regulations, if you want to look at them).
Despite the risks which can be associated with observational research, there is much that has and to
be learned by these studies. None of this discussion is to dissuade you from participating, it is merely
to help you make an informed choice.
As a research scientist who takes care of patients, I NEED you to help us take better care of
individuals with Organic Acidemias. As you know, many fundamental questions about these disorders
still exist. We do not know the natural history of these disorders well. We do not have adequate
medications and interventions. We cannot tell you whether you or your care is going to be severe or
mild, have a decompensation in the next 2 weeks or not, or develop a particular complication. This is
not to say that we are not getting better, but more information is necessary. Thanks for all the help
you provide to us.
understand your family’s disorder. We are going to start a new section to the newsletter to talk about
research.
Let’s start with what research is. It is a system or process in which the goal is to better understand
something in the world around us. We divide research into clinical (that which affects the patient
directly) and basic (that which studies fundamental processes, e.g. studying the Kreb’s cycle or how
cells talk to each other). Today we are going to talk about a subset of clinical research. As part of this
discussion, we are going to examine the expected benefits and risks from this subset of clinical
research--observational studies.
The two big, most basic categories of clinical research, basically research that which is designed to
understand the natural course of a disorder (observational) and that which tries to impact that natural
course (interventional). Sometimes, the research protocol tries to do both, especially if little is known
about a particular disorder or if a disorder is generally lethal to almost all with the disorder.
So from this point forward, we are going to ignore issues of interventional studies—these are clinical
trials in which an intervention, like a medication or a device is tested to see if it works better than
current practice and address these at a future date, and focus on observational studies.
Observation studies have several flavors, the shallow, the medium and the deep evaluations. In
general, observational studies collect information about an individual (like an individual with an
organic acidemia and their family). They can collect information at one particular time in many
individuals or can follow an individual or cohort of individuals over time. The best designed studies to
gather natural history—what happens in the disorder with current interventions over time---follows
individuals through time, but these can take a long time so some studies are designed to look at many
individuals who are at different points in their disorder at one moment in time and makes assumptions
about impact of time on the disorders. Either of these studies can be shallow, medium or deep in
terms of how much information they gather.
A study which is designed to take a shallow look at a disorder looks for the most basic facts (i.e.
disorder, genotype, current health) and often is fairly short in length (and so can take less time to
complete the initial forms). This can gather information once or over time from the same individuals.
The benefit from this study is that it can provide a “google earth” view of the disorder and takes little
time from each participant to gather the information (like minutes). The problem is it is a shallow
look at the disorder and so rare complications or occurrences are unlikely to be identified.
A study which is more in depth (a deep information study) tries to examine every possible thing about
a disorder and collects a lot of data on each participant often over the course of days. Often times this
type of study also gathers biological specimens (i.e. laboratory, biopsy, etc.) and radiological data (i.e.
X-ray, MRIs, etc.). Dr. Venditti’s natural history studies (for MMA and PA) at NIH are an example of
this type of study. Again individual participants can be studied over time (like Dr. Venditti’s studies) or
deeply once. This is like getting a magnifying glass out on a walk through the neighborhood and
studying as much as possible as closely as possible. You learn lots about lots of things but it takes lots
of time and produces much data. The benefits with these studies is rare occurrences or small changes
are more likely to be identified. The disadvantage is it takes lots of time from the participant and is
very expensive for the researcher.
The type of study which sits between these two in the continuum of studies is the medium study. It is
like the view one has walking down the street in one’s neighborhood, some detail (the designs on the
houses), but not lots of specifics (no idea how many ants on the sidewalk). Our natural history
registry with NORD is an example of this type of study. It does not gather as much information as the
deep study, but more than a shallow study. It tries to gather enough information that common rare
occurrences can be identified, but has less time commitment (more measured in an hours).
Each of these observation studies have some risks. Consent to participate in research of this type
should include a list of the risks identified and possible mitigations for these risk.
Privacy and confidentiality are two of the biggest risks with observational studies. Those observational
studies which include laboratory and radiology as a component also have risk associated with these
procedures.
Some common privacy risks in these types of studies include 1) how safe are my data and will
someone outside the study be able to see them and identify that it belongs to me, 2) can I be
identified by my data and how are my data being protected? Data here can mean your name, your
address, connecting the disorder to you, your health history, your date of birth, etc. You can
understand why these privacy issues could be concerning and why you as a participant (or your care)
should be aware of this risk.
Most reputable registries and natural history studies tell you how and where your information is stored
and protected as part of the consent. They are aware of the concern. In fact, the European Union
has just required much more strict privacy rules for any registry or natural history study which has
anyone who is lives in the EU or storage in the EU (it is called the General Data Protection
Regulations, if you want to look at them).
Despite the risks which can be associated with observational research, there is much that has and to
be learned by these studies. None of this discussion is to dissuade you from participating, it is merely
to help you make an informed choice.
As a research scientist who takes care of patients, I NEED you to help us take better care of
individuals with Organic Acidemias. As you know, many fundamental questions about these disorders
still exist. We do not know the natural history of these disorders well. We do not have adequate
medications and interventions. We cannot tell you whether you or your care is going to be severe or
mild, have a decompensation in the next 2 weeks or not, or develop a particular complication. This is
not to say that we are not getting better, but more information is necessary. Thanks for all the help
you provide to us.
