A review of the PhD thesis Alcohol use, alcohol polygenic score and cognition in schizophrenia,

schizoaffective disorder, and bipolar disorder

The PhD thesis manuscript by Atiqul Mazumder entitled “Alcohol use, alcohol polygenic score and
cognition in schizophrenia, schizoaffective disorder, and bipolar disorder” comprises three articles
published in the same moderate-level international scientific journal. While the contents of the
articles could have been summarized in two articles, as they address very closely related study
questions, often articles in the field do have very focused structures. The study questions address
study topics that are scientifically relatively novel and have both scientific and public health
significance. The study sample is large and well suited to address the study questions. The author
also answers the study questions with justified methodology.
However, the thesis summary requires substantial revisions before its acceptance can be
recommended. Both the level of scientific reasoning, in particular in terms of methodological
assessment of scientific evidence, and the structure and details of the text are not on the level
required by a PhD thesis. The candidate needs to provide a sufficient, critical and methodological
assessment of the quality of available evidence in the different topics addressed, summarize and
evaluate the used methodology and results of the previous studies in a consistent and clear manner.
The methods and results sections of the summary describing the results of the current thesis also
need substantial revisions. These sections should stand on their own rather than constantly referring
to material published in the original manuscripts. The candidate needs to do a better job in
summarizing the key methods and results and the validity of the assessment methods used here. The
text can put together aspects of the different articles and provide additional new tables and figures
displaying the key findings. The candidate also needs to provide a more thorough discussion section
where the current findings are clearly put in the context of previous literature and strength and
weaknesses of the current and previous studies are evaluated in a scientific manner. The references
section needs to follow a solid structure for all references and list them in alphabetical order. There
are also some structural inconsistencies in the text for which revisions are needed.
Next follows comments on the different subsections of the thesis.

Abstract:
The Finnish version of the abstract needs substantial revision and language corrections by a native
Finnish speaker. The conclusions of the abstract do not directly follow from the results presented. If
there are deficits in memory function associated with alcohol use in female patients with psychotic
disorders, these should also be given some emphasis in the conclusions. The sex-specificity of the
findings could also be noted here.

Introduction
In the Introduction, the candidate needs to be able to evaluate critically the quality of the available
evidence on his study topic and related study questions rather than solely listing key findings of
previous studies without providing any assessment of the methods of the studies or the reliability,
generalizability and validity of their methods. The summary should provide the reader a critical,
scientific assessment of the available evidence rather than solely listing results of previous studies.
While the candidate is right in stating that the current study topic has not been the focus of much
previous research, the candidate needs to show the skills to evaluate critically and scientifically
assess the previous evidence of related topics based on which the candidate justifies the need for the
current research.
In the epidemiology section, a more detailed discussion about the multiple etiological risk factors
for schizophrenia, schizoaffective discussion should be provided. There is substantial amount of
research evidence on this topic. While not the main topic of this thesis, given the focus also on
PRSs, this topic should be elaborated upon more. Heritability estimates for the different mental
disorders should be given and they should be based on more recent literature and combine findings
from both GWAS and twin studies. Discussion about the etiology of schizoaffective disorders
should also be provided. Much more literature is described for the etiology of bipolar disorder, but
also here the text should be more systematic. For all these disorders, both the role of hereditary and
environmental risk factors is now well-proven in their etiology and a more detailed, albeit brief
discussion on this topic should be given in the text.
Regarding prevalence rates, the author should summarize the available evidence rather than list all
individual studies. In mortality and other epidemiological consequences are provided for one
disorder, they should be provided for all of them. The phenotypic description for bipolar disorder
should be clearer and follow a similar order than the other mental health phenotypes. The author
should first give the descriptions of the symptoms related to the disorder and only thereafter briefly
describe what has changed across time in the definition of the illness. When describing the
diagnostic criteria for schizophrenia, the candidate should specify how and when substance use is
used as an exclusion criteria and how this may influence any associations between the phenotypes.
In the time the diagnoses were extracted for the participants, ICD-10 was in use in Finland. If the
diagnoses were made based on these criteria, they should be mentioned as well.
The text: Schizophrenia is associated with marital status especially in males and unmarried are
frequently affected (Hung et al., 2017). would suit better in the Epidemiology of schizophrenia
paragraph.
The different diagnostic definitions for the psychotic and substance use disorders studied should be
given in a table rather than providing very lengthy in-text descriptions. Then the key symptoms
could be described in text. For example, the description of symptom of AUD in DSM-5 is very
lengthy. A subheading: Epidemiology of alcohol use disorders should be provided. More
information about the epidemiological correlates and etiology of alcohol use disorders should be
provided.
Regarding cognitive function in the different psychotic disorders and in relation to substance use,
the author should do a better job in scientifically summing up and evaluating the available evidence
on a study topic rather than listing individual studies or meta-analysis separately. What can be said
of the available evidence on the topic? The author should summarize the available evidence and
make conclusions about what is known and what is not. For example, begin with providing the key
meta-analysis on the study question and add additional findings only if necessary. Cognition
comparisons in different mental disorders could be given under a separate heading, summing up the
available evidence in different disorders and then providing direct comparisons.
In the paragraphs 2.8-2.9: Comorbidities of the psychotic disorders with alcohol use disorders for
all psychotic disorders and their comorbidity with alcohol use disorders, the text should follow a
consistent clear order and pattern rather than listing a set of study findings after another. The author
should first describe all findings on the prevalence of AUD in question, then list associated risk
factors or sociodemographic correlates and then describe the long-term outcomes or consequences
of this comorbidity.
Also in chapters 2.10 and 2.11, the author needs to without providing a clear synthesis of the
available evidence, pointing out the methodological weaknesses and strengths of the available
studies and meta-analysis. Currently the text only lists findings of individual studies and meta-
analysis without any critical assessment. The text should more clearly show to the reader how the
author sums up the available evidence and what can be concluded based upon these studies. If there
is no clear methodological strengths of the individual studies described, the synthesis should start
from reviewing available meta-analyses and systematic reviews and only then move to describing
key individual studies if necessary.
The paragraph 2.12. should also follow a clearer structure. When describing the lack of previous
studies on a certain study topic, the author should be more cautious in his/her statements and use
phrases such as “To my knowledge, there are no studies on..:”
The theoretic and biological frameworks for cognition and alcohol use could precede the findings in
different specific disorders.
The paragraph 2.14. should also use citations to relevant scientific literature. This kind of summing
up of available evidence and critically evaluating the methodology of the available studies
presented in this paragraph would also markedly improve all the above paragraphs where previous
findings are only listed one after another.

Research Objectives
The research objectives paragraph 3.3. should also include hypothesis and clearly stated study
questions. If the author thinks there is no basis for any hypothesis, a justification for this conclusion
needs to be provided. However, based on the later parts of the text, it seems evident that the author
had clear hypotheses in mind when planning the studies.

Methods
The study sample is of sufficient size to answer the study questions. The used statistical methods
are solid choices to address the study questions. However, in the text of the methods section, the
author needs to do a much better job in describing the methodology used in the studies of the
current thesis. The validity of the instruments used along with more consistent and precise
descriptions of each phenotype needs to be provided. Currently, the text does not follow a clear
structure and it needs to be organized better.
As stated briefly above, in both the Methods and Results sections, the candidate should do a better
job in summing up key methodology and results of the individual studies of the thesis. This should
be a summary of the thesis rather than a text where text paragraphs from the original articles are put
one after another. Currently it seems that many parts of the text were copied from the articles. The
methods section of the summary should sum things together across the different studies rather than
repeating the text from the individual articles word by word. This is not good scientific practice.
The author should in the methods section of the summary provide a synthesis of the methods and
results of the thesis, in own words. While this is always needed, the current thesis with comparable
methodology across the different sub-studies would provide an optimal setting for summarizing key
methodology across studies. The candidate needs to describe the overall methodology of the thesis
in his/her own words.
Next follows comments on the subsections of the methods part of the text:
A concern is the representativeness of the analyzed sample compared to the original SUPER study
population. Please provide attrition analyses-did the included and excluded study members differ in
key study characteristics? Please also give more information about the SUPER sample. The text
should list sample characteristics, demographics, number of participants. How many of the
participants had each disorder in the original SUPER sample? Were healthy controls enrolled to the
study at all?
The lengthy description of statistical solutions for the use of age of onset vs. age as a covariate in
the analyses should be shortened. It is also questionable whether it is now in the most suitable place
in the text.
The different diagnostic paragraphs in the Methods section should follow a similar structure and
summarize similarities and differences across sub-studies. Now the paragraph on alcohol use
disorders enlists diagnostic criteria and the one on bipolar disorder exclusion criteria. The author
needs to be more consistent in his/her writing, either providing these details in all paragraphs or
then describing the diagnostic criteria only in the Introduction section, for example. Why is the
usage of DSM-III-R criteria for bipolar disorder mentioned in the schizophrenia paragraph? Why is
the text completely different in the AUD paragraph?
Importantly, reasons for exclusion in the different sub-studies should be thoroughly justified and the
author should state whether the same exclusion criteria were used for all studies. Was it not so that
the same exclusion criteria were used for all psychiatric disorders? If so, why are these exclusion of
severe cases criteria then listed only in the paragraph 4.7.3 and not as referring also to schizophrenia
and schizoaffective disorder? Were similar exclusion criteria of hospitalized patients used for all
disorders? Or were inpatients included for the patient groups of schizophrenia and schizoaffective
disorder? Or why is this exclusion listed only for bipolar disorders? How were comorbidities across
schizophrenia spectrum and bipolar disorders handled in the studies 1 and 2 on hazardous drinking
and AUD in the different psychotic disorders? If this description is given at all in the 4.7. section, it
should refer to all psychiatric disorders, not only to bipolar disorder.
Psychometric properties of both the register data used for diagnoses and of the psychometric tests
needs to be provided in the Methods section. Please cite the studies validating the diagnoses of
schizophrenia spectrum and bipolar disorders in the Care Register for Health Care. These studies
are essential methodological references for the current thesis. Please provide more information on
the psychometric properties of the neurocognitive tests used. Have they been validated? Was there
any psychometric data available for the current study participants? For the PAL-test, please cite the
NFBC study where it was originally used and the norm data created and cite at least some NFBC
studies. Please provide also validation references for the AUDIT scales used in the current study. Is
the MHI-5 validated? Was the cutoff score for depression below or above 72 points?
The author should clearly describe which published GWAS studies the PRSs for hazardous drinking
were based on. Or did the author create the scores based on their own data? The author states “. We
chose the hazardous drinking PGS based on their correlation with hazardous drinking in our study
population”. Please provide statistics for such statements. How strong was the correlation?
While the used statistical analyses are well justified and suitable to address the study questions, the
reviewer is left to wonder whether the findings would look similar if the AUDIT scale was used as a
continuous rather than categorical index of alcohol use? What about the use of the other mentioned
cutoff scores for this scale? Please also provide a rationale for the use of depressive symptoms as a
covariate when first describing the choice of this covariate.
The candidate also needs to be careful when using the terms covariates and confounders and follow
the precise definitions for these. You cannot know whether a certain factor is a confounder before
looking at the data.

The Results
The results section of the thesis summary should read on its own rather than solely referring to
tables of the articles or directly providing the same text as in the articles. All key findings and
associations between exposures and outcomes should be described and summarized here rather than
referring to the tables of the manuscripts. Please describe the main findings along with necessary
statistics. Furthermore, when similar findings have been observed for all the different
neuropsychiatric disorders, it may be beneficial to present these under the same heading rather than
repeating the same message in three sentences.
New tables can also be added to the summary to efficiently describe the results. For example, the
reader cannot be expected to find the results of the thesis in the supplementary material of the
published articles. Please describe all essential findings here in the results section of the summary,
possibly with tables combining findings or sample characteristics across sub-studies.
The thesis summary does not have to follow precisely the order of the manuscript and would benefit
from its own tables and from providing statistics for all the reported associations. Put more
emphasis on the main findings and summarize background associations in tables and in a more
concise manner.
For all key outcome phenotypes, please provide both unadjusted and adjusted results in the text. If
an association is present before adjustment for numerous covariates, there is still an association that
needs to be described. Then it becomes essential to figure out which of the covariates explained the
association. Table 2 of the first article clearly shows many group differences that vanished when
adjusting for the different covariates. It would be important and very interesting to know which
covariates were driving the univariate associations. It also remains somewhat unclear from these
tables whether hazardous drinking or alcohol use disorders were associated with better or worse
cognitive performance in these univariate analyses.
When describing the background associations, please state out the direction of the association for all
covariates, including household type. It would be worthwhile adding a combined table of the
associations of the covariates with the phenotypes of interest here in the thesis summary rather than
referring to supplementary tables of the original articles.
At times, the vocabulary of the text should be improved. It remains unknown, what is meant by the
comment “The effect sizes were in line with our results “. A phrase “when we confounded for” is
not a solid description of the analyses-the text should read, “When we adjusted for”. The author
should describe whether lower reaction time indicates better or worse neurocognitive function.
When speaking of time, “lower” is not the best term to be used.
Discussion
The opening paragraph of the discussion section is vague and inconsistent. Where there associations
or were there no associations. The sentences following each other give an opposite interpretation of
the findings.
Throughout the discussion section and particularly when comparing current findings with previous
ones, the author needs to provide a solid methodological comparison and assessment of the current
and previous studies on neurocognitive functioning and AUD or hazardous drinking in the different
studied psychotic disorders rather than solely listing their results without no methodological
assessment. The author also needs to be able to sum up findings from multiple studies rather than
listing each study one by one. The author also needs to provide some discussion why s/he thinks the
current findings contradict or are in line with previous ones. The used comparison groups may also
be essential here. The current study did not use any healthy comparison group.
The author should also discuss the sex-specificity of the findings more thoroughly. There are
multiple significant associations in women but none in men. Why does the author think this is the
case? The lack of such a discussion is a clear weakness of the discussion section and such a
discussion needs to be provided. Is there previous evidence supporting such sex differences? Were
there any interactions by sex?
Also in the discussion section, when making statements about the lack of previous studies on a
certain topic, the author needs to be much more humble in stating that no such studies exist
according to his/her knowledge. The author makes one such statement but such phrasings should be
used more consistently.
In the paragraph 6.3: Strengths, the author needs to specify why s/he considers certain topics
mentioned in this paragraph to be study strengths rather than limitations. There are numerous such
statements where it remains unclear why this would be a study strength. For example, the author
states, “our inclusion criterion of independent living excluded hospitalized patients, so patients with
severe manic or depressive episode were not included. If this was a study limitation, then the text
needs to be moved under that heading. Another inclusion criterion was the ability to give written
informed consent which also restricted inclusion of bipolar disorder patients with severe manic or
depressive symptoms” sets forth a question how is this a study strength rather than a factor limiting
the generalizability of the findings? Furthermore, why were the same exclusion criteria not used for
schizophrenia or schizoaffective disorder? Numerous schizophrenia patients are also hospitalized. It
remains unclear whether they were included or excluded from the study. This needs to be described
in the text.
Generally, the author discusses the limitations of the current study well. However, the first
paragraph of the limitations section does not belong in this section. The limitations section needs to
discuss the limitations of the current study rather than discussing reasons for positive findings in
previous studies. Such reasons need to be discussed earlier in the text, when comparing current and
previous findings. The first paragraph needs to be thus moved elsewhere. The author should also
point out the lack of a healthy comparison group in the current study as a major study limitation.
Importantly, also the strengths and weaknesses sections of the discussion include some text, which
seems to be copied from the article texts. Rather than copying the text from the original published
articles, the summary should list the strengths and weaknesses of the studies across studies in the
authors’ own words and putting broader reflection on the topic at hand.
Conclusions and Clinical Implications:
The clinical implications paragraph should be more thorough and precede the conclusions
paragraph, unless otherwise stated in the instructions. In the conclusions section, when referring to
previous studies, please provide references. There were also some instances where neurocognitive
functioning was associated with the alcohol use phenotypes-these should also be discussed here, as
well as the sex-specificity of some of the findings.
Importantly, the candidate needs to point out more evidently the novelty and scientific and public
health relevance of the current research. What this study adds to the scientific literature, why was it
done and why is this an important study?

Structural Comments Regarding the Thesis Manuscript Text

The reference list needs to follow an alphabetical order when listing the references. Please be
careful in ordering the references in the correct order. In the reference list, all studies also need to be
cited in a similar manner, referring to a standard citation system (APA, Vancouver style etc.). The
author cannot use abbreviations of journal names for some citations and full names for others. In the
text, please open all abbreviations the first time they are mentioned and use the abbreviations
consistently thereafter. The language of the thesis text would also generally benefit from further
proofreading by a native English speaker.
Summary statement
The thesis addresses a novel, important research question. The three articles of the thesis are
published in an international, moderate-level scientific peer-reviewed journal. The methodology
used is suitable for addressing the study questions.
However, the summary of the thesis does not show high-level scholarship or expertise of the
candidate and requires substantial revisions to all its subsections to constitute a summary for a PhD
thesis. In the summary, the candidate needs to show scientific expertise and prove the scientific
skills to critically evaluate and summarize the available previous evidence and assess and
summarize the methodology, results, strengths and weaknesses of both previous studies and his/her
own work. Currently, the summary only lists studies after another without providing sufficient
summaries or methodological or other scientific assessments of the available evidence or the
applicant’s current work.
There are also several structural issues that require substantial revisions. More details of the
methodology of the current study need to be provided, especially considering the similarities and
differences between the sub-studies. The methods and results sections of the summary should
summarize similarities and differences across the different sub-studies of the thesis and clearly
describe essential results and methodology and the validity of the methods used. The format of the
reference list does not consistently follow a clear citation format and needs revisions. The
implications of the study findings, both unadjusted and adjusted ones need to be given more
emphasis and the scientific and public health relevance and importance of the current thesis need to
be pointed out more clearly.
Taken these strengths and weaknesses of the thesis manuscript into consideration, the pre-examiner
states that a new pre-examination is needed. In its current form, defense permission cannot be
granted to the thesis. Major revisions are required for the thesis after which the defense permission
can be reconsidered.

______________________________
Marius Lahti-Pulkkinen,
Academy Researcher, Docent, Ph.D.
Helsinki, March 15, 2022