Since studies eat money, do you have a plan for how you might raise additional funding once the very early stage funding dries up? It seems the value here is bound up with enabling future studies, so understanding the funding environment and costs of potential future studies seems important in evaluating whether to fund the foundational research.
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Psychosis in velocardiofacial syndrome (DiGeorge/22q11.2 deletion syndrome)
Not fundedImpact certificate
$0raised
$2,000valuation
Longer description of your proposed project
Velocardiofacial syndrome (DiGeorge syndrome, 22q11.2 deletion syndrome) is a fairly common (1/4000), probably underdiagnosed genetic disorder. Its famous characteristic is that at some point clustering around young adulthood, ~30% of people with VCFS develop chronic psychosis. "Relatively early-onset chronic psychosis" is diagnosed as schizophrenia, so VCFS is assumed to be "the biggest genetic risk factor for schizophrenia". I've dived fairly deep into the literature on this, and I'm unsure how to best think about this psychosis, or whether it can be treated as a "schizophrenia-spectrum/schizotypal-spectrum" psychosis:
Schizotypy, a lifelong set of personality and developmental traits associated with the expanded "schizophrenia spectrum", is underresearched in VCFS. Positive schizotypy (subclinical psychotic traits) doesn't seem to be particularly high. Negative schizotypy (a heterogeneous group of introversion- and anhedonia-related factors) shows up as high, but most of this loads on "decreased ideational richness" -- a trait strongly associated with low IQ, and people with VCFS have lower average IQs.
VCFS is genetically homogeneous, but VCFS psychosis is very heterogeneous clinically and has extreme variance in age of onset, affective/non-affective traits, etc. These don't seem to correlate well with things they correlate with in other populations (e.g. gender).
Children with VCFS don't differ significantly in psychological traits or psychopathology from other children matched for IQ.
There is zero correlation between VCFS psychosis and autism spectrum disorder diagnosis, which no hypotheses of the autism-schizotypy relationship can accommodate well.
Most importantly, VCFS psychosis seems to be dementing, or possibly dementing. This is absolutely atypical of schizophrenia, or of any other psychosis that onsets in early adulthood in the general population. While we're held back by tiny sample sizes, numerous studies suggest impossibly large declines in IQ and adaptive skills post-onset, and/or significant raw score declines on IQ tests shortly before onset (not just decline of IQ itself, which usually doesn't represent raw score changes).
I want to research schizotypy in VCFS and the lifetime presentation of VCFS psychosis in greater depth, in order to improve our understanding of its relationship with the schizotypal spectrum. One of my current formulated plans is to study four groups of young adolescents (VCFS, controls w/ VCFS-matched IQ, controls w/ normal IQ, and people with SZ first-degree relatives) and survey them on schizotypy, personality, and psychological distress measures, in order to see how the numbers shake out. Risk comparisons of adolescents with VCFS to the second and fourth groups there are pretty sparse and have often turned out results incompatible with one another. I want to see what results multiple distinct instruments turn out here, what weird correlations pop up, and exactly how the positive schizotypy thing shakes out.
I also want to perform more cytogenetic screening surveys for VCFS -- while there are a lot for it in SZ samples, there are interesting missing groups. Given the often dementing course of VCFS psychosis, I want to see if the 22q11.2 deletion is overrepresented amongst people diagnosed with early-onset dementia, particularly with low premorbid IQ or a previous psychosis diagnosis. I also want to confirm the dementing thing in larger samples (barely any research on VCFS psychosis looks at its long-term course, so while we've found older adults frequently have impossible-in-SZ large IQ and adaptive decline, the samples here are fairly small, and there haven't been any e.g. structured interviews with people with 20+ year VCFS psychosis and their caregivers) and see what alternative treatments might alleviate or prevent symptoms -- there's some evidence that VCFS psychosis can respond to atypical treatments.
This research can hopefully have great consequences for people both with and without VCFS. If VCFS psychosis is a dementia that's unrelated to the schizotypal spectrum, then research on SZ that uses it a lot (e.g. basically all animal models) is invalidated, which would be annoying for those guys but positive in the long run. It might be partially mitigatable, or preventable, by treatments that alleviate/slow symptoms in dementia. It would also prevent chasing down further dead ends in SZ research that come from VCFS. If it is related to the schizotypal spectrum, that opens up the different questions of why so much of its presentation is completely different, which could also have fruitful results.
Describe why you think you're qualified to work on this
I'm an extremely-early-career, functionally-independent researcher in psychology interested in the autistic and schizotypal spectra, and in particular how genetic syndromes interact with them (ASD is frequently diagnosed in the syndromic context, but it's unclear how much of this looks anything like what Kanner or Asperger wrote about). My first paper (a literature review on a subject in this sphere) is currently under review. I'm hoping to pursue this as I enter graduate studies and progress in my career; for various reasons, I've had to do a lot of things alone/bootstrap to an unusual degree, and I'm finally running into things I can't do as "literally one guy with no support or funding of any sort". I'm aiming to get into a PhD program, and need support/funding I don't have yet.
Other ways I can learn about you
https://vaticidalprophet.substack.com/
How much money do you need?
Studies eat money. My institution is not one that has any research funding, or any...research (hence why I'm essentially an independent researcher with a university email). This means I need to pay my own way, 100%, when it comes to things, things like open-access article processing charges, orchestrating studies, getting private IRB/HREC approval, etc.
My minimum funding for "any money released" is $2k, which can't realistically do much of this, but could cover something like "an APC for a very small study or review". My funding goal is $50k, which sounds more realistic for at least one of the above-mentioned studies and for some amount of pre-grad-school/grad-school funding. This is still a very small grant in medicine. I know where I am in the academic pecking order, which is "not even on it, realistically". I think this is an important goal and am willing to sacrifice for it.
Links to any supporting documents or information
Some citations of interest:
Evers, L. J. M. (2015). 22q11.2 deletion syndrome: Intelligence, psychopathology and neurochemistry at adult age [Ph.D., Maastricht University]. https://doi.org/10.26481/dis.20151214le
This is the major research on dementia in VCFS psychosis. It's pretty bizarre (60-point IQ drops, loss of basic motor skills, etc) and exceptionally telling, but hasn't really been looked at since, and there are concerns (e.g. scales of premorbid and postmorbid IQ aren't equivalent, though this is functionally impossible to avoid when someone's IQ drops below 40ish given the discordance in scales for severe ID).
Fanella, M. (2021). Neuropsychiatric features and genetic aspects in 22q11.2 deletion syndrome [Ph.D., Sapienza Università di Roma]. https://iris.uniroma1.it/retrieve/e383532c-0d11-15e8-e053-a505fe0a3de9/Tesi_dottorato_Fanella.pdf
A more recent look at long-term IQ associations with VCFS psychosis, replicating a major overrepresentation of severe intellectual disability (not found in either recent-onset studies or studies of psychosis in ID without VCFS).
Duijff, S. N., Klaassen, P. W. J., Veye, H. F. N. S. de, Beemer, F. A., Sinnema, G., & Vorstman, J. A. S. (2012). Cognitive development in children with 22q11.2 deletion syndrome. The British Journal of Psychiatry, 200(6), 462–468. https://doi.org/10.1192/bjp.bp.111.097139
Children with VCFS sometimes (not even that rarely?) have absolute/raw-score cognitive decline, rather than 'just' slowing of raw development resulting in IQ decline. This is not a thing that happens in children, generally.
Schneider, M., Armando, M., Pontillo, M., Vicari, S., Debbané, M., Schultze‐Lutter, F., & Eliez, S. (2016). Ultra high risk status and transition to psychosis in 22q11.2 deletion syndrome. World Psychiatry, 15(3), 259–265. https://doi.org/10.1002/wps.20347
People with VCFS who fit UHR criteria develop florid psychosis at about the same rate that people without VCFS do, despite this being...really weird? (UHR transition to florid psychosis is pretty low, famously, which I sure have a lot of thoughts about.) People with VCFS without UHR criteria develop florid psychosis more than people in genpop who don't fit UHR criteria do, though this is a small increase and needs to be looked at more.
Yu, S., Graf, W. D., & Shprintzen, R. J. (2012). Genomic disorders on chromosome 22. Current Opinion in Pediatrics, 24(6), 665–671. https://doi.org/10.1097/MOP.0b013e328358acd0
Passing mention of "overlapping similarities to dementia", including memory problems. This is tantalizing -- Shprintzen is one of the like seven different people who have a claim to discovering VCFS, to the point "Shprintzen syndrome" is on its infinitely long list of historical names. If he says this, I'm listening.
Fonseca-Pedrero, E., Debbané, M., Schneider, M., Badoud, D., & Eliez, S. (2016). Schizotypal traits in adolescents with 22q11.2 deletion syndrome: Validity, reliability and risk for psychosis. Psychological Medicine, 46(5), 1005–1013. https://doi.org/10.1017/S0033291715002500
Monks, S., Niarchou, M., Davies, A. R., Walters, J. T. R., Williams, N., Owen, M. J., van den Bree, M. B. M., & Murphy, K. C. (2014). Further evidence for high rates of schizophrenia in 22q11.2 deletion syndrome. Schizophrenia Research, 153(1), 231–236. https://doi.org/10.1016/j.schres.2014.01.020
Both these studies find at-least-arguably lower positive schizotypy in some scales than controls. Both are pretty small samples, so significance is a mess. I want to recruit/study larger international samples, which is the only way we're going to get a solid idea here.
Prinzie, P., Swillen, A., Vogels, A., Kockuyt, V., Curfs, L., Haselager, G., Hellinckx, W., Devriendt, K., Onghena, P., Van Lieshout, C. F. M., & Fryns, J. P. (2002). Personality profiles of youngsters with velo-cardio-facial syndrome. Genetic Counseling, 13(3), 265–280.
Children with VCFS have basically unremarkable Big Five profiles compared to children with other common genetic syndromes, i.e. there's nothing in there that implies a later susceptibility to schizotypal psychosis. Schizotypy and Big Five is a bit of a mess, but the uncomplicatedly much lower Openness here than control children without syndromes is eyebrow-raising. IQ is a complex factor here, which is why I want to study multiple control groups, including an IQ-matched one, and see how people with VCFS compare.
Feinstein, C., Eliez, S., Blasey, C., & Reiss, A. L. (2002). Psychiatric disorders and behavioral problems in children with velocardiofacial syndrome: Usefulness as phenotypic indicators of schizophrenia risk. Biological Psychiatry, 51(4), 312–318. https://doi.org/10.1016/S0006-3223(01)01231-8
Childhood psychopathology in VCFS is not different to IQ-matched children without syndromes, i.e. there isn't an obvious signal in the noise of psychosis-proneness.
Talan, J. (2021). Doctors said the boy was suffering from teenage psychosis. What he really had was a rare genetic condition. Washington Post. https://www.washingtonpost.com/health/teenage-psychosis-genetic-condition/2021/04/30/65133794-6be5-11eb-9ead-673168d5b874_story.html
This is a very, very weird article, in which two of the world's major experts on VCFS declare confidently that it is not schizophrenia.
Estimate your probability of succeeding if you get the amount of money you asked for
Best definition of success is "funding permits multiple studies using far larger patient and comparison populations than previous research, which produce much more interpretable conclusions about currently-understudied elements of the VCFS psychosis phenotype". I think this is pretty likely (80%?). It might be higher than that; I'm pricing in some pessimism.
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vaticidalprophet
8 months ago
@Jason Thanks for asking! I'm planning to use this as a springboard. Starting with early, relatively-achievable studies that can produce multiple papers allows for a body of research that I can point to in the future. For instance, with my planned study comparing young people with VCFS to multiple control groups, I intend to investigate:
1: Scores on traditional 'clinical' scales (e.g. measures of schizotypy)
2: Scores on less 'clinical' scales, like traditional personality scales (which correlate well with these, but tend to be siloed in the literature)
3: "Mischievous responding", a problem with studying adolescents and young adults where people intentionally give wrong answers to questions; the framework of my intended study makes this uniquely easy to look at, because of the existence of multiple exclusionary criteria (e.g. family histories of certain disorders), which allows for catching many mischievous responders with "do you have a family history of [exclusionary condition]?" and similar(1)
4: Whether mainstream scales actually work in this population at all (some have been validated, but others haven't), and investigating alternative scales that would be applicable to multiple populations, making the research usable far more broadly than its original remit(2)
These findings split naturally (i.e. without "salami slicing") into several publications -- mischievous responding and its correlates, for instance, are interesting to a different audience of people than the results on the clinical scales. Nonetheless, they can all be done in the same research project and naturally amount to about 2-3 surveys. This allows for an early-stage project like that to be completed with much less money than a traditional large health-sciences project would require.
This is useful for navigating applications to multiple future areas (e.g. doctoral clinical psychology programs, funding dedicated specifically towards early-career researchers in the health sciences). Because my institution doesn't have the kind of research environment that's used to navigating traditional grants, or prestigiously-named PIs, there are pretty serious barriers to traditional funding bodies. I'm hoping that I can get a chance with a culture less tied up in name recognition, and parlay success that comes out of this into breaking into the more conventional environment of academia.
(1): Mischievous responding is a huge problem in large public health surveys, and we can suspect with near-certainty it's a similarly huge problem in other surveys of AYAs -- but the public health surveys where it comes up most severely, by definition, don't have exclusion criteria. A study where, for instance, a diagnosis of an autism spectrum disorder is exclusionary has the significant upside that "are you autistic?" is both a common mischievous-response and a question where we know any yes answers are lying. We don't understand much about the demographic correlates or response patterns of mischievous responders (aside from that males do it more often), and a study that silently tracks the responses of confirmed mischievous responders has significant value for understanding it in larger health surveys.
(2): There is a lot of unfilled demand for personality and mental health scales that we know with certainty work for people with intellectual disabilities.